SDHA

protein-coding

succinate dehydrogenase complex flavoprotein subunit A, the group of Mitochondrial complex II: succinate dehydrogenase subunits

Gene summary

This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

Previous symbols:

SDH2

MANE transcript

NM_004168.4

Inheritance

AR, AD

ClinVar variants

P:399U:1518B:817

Top phenotype

Pheochromocytoma/paraganglioma syndrome 5; Gastrointestinal stromal tumors; Cardiomyopathy, dilated, 1GG; Neurodegeneration with ataxia and late-onset optic atrophy; Mitochondrial respiratory chain complex II deficiency, nuclear type 1

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr5:218,303-257,082

External References & Databases

Ensembl (ENSG00000073578)

Transcript & Mutation Effects

hg38 • Region Span ~38.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SDHA and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 8, 2019. 14 articles were reviewed. SDHA was first reported in relation to autosomal recessive Leigh syndrome spectrum in 1995 (Bourgeron et al., PMID 7550341). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 7 probands in 6 publications (PMIDs 7550341, 10746566, 16361598, 16798039, 22972948, 24781757). This gene-disease association is supported by the known protein interactions, model systems, and rescue. The mechanism for disease is complex II deficiency. In summary, there is moderate evidence to support the relationship between SDHA and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 13, 2019 (SOP Version 6).

mitochondrial complex II deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009641

Submitter: Orphanet

hereditary pheochromocytoma-paragangliomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: Orphanet

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

mitochondrial diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SDHA* and autosomal dominant primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 11, 2025. The *SDHA* gene encodes the flavoprotein subunit of complex II (succinate dehydrogenase), which plays an essential role in both the citric acid cycle and in the electron transport chain by catalyzing the oxidation of succinate to fumarate. The *SDHA* gene was first reported in relation to autosomal dominant primary mitochondrial disease in 2000 (PMID: 10976639). *SDHA* has been associated with four disease entities to date; autosomal recessive cardiomyopathy, dilated, 1GG [OMIM# 613642], autosomal recessive mitochondrial complex II deficiency, nuclear type 1 [OMIM# 252011], autosomal dominant neurodegeneration with ataxia and late-onset optic atrophy [OMIM# 619259], and autosomal dominant pheochromocytoma/paraganglioma syndrome 5 [OMIM# 614165]. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, this Expert Panel found a difference in molecular mechanism, inheritance pattern, and phenotypic variability among several of these entities. Therefore, the two autosomal recessive disease entities (autosomal recessive cardiomyopathy, dilated, 1GG [OMIM# 613642] and autosomal recessive mitochondrial complex II deficiency, nuclear type 1 [OMIM# 252011]) have been lumped into one disease entity, renamed autosomal recessive *SDHA*-related primary mitochondrial disease, and curated separately. The autosomal dominant disease entities (autosomal dominant neurodegeneration with ataxia and late-onset optic atrophy [OMIM# 619259], and autosomal dominant pheochromocytoma/paraganglioma syndrome 5 [OMIM# 614165]) have been split and curated separately. The autosomal dominant neurodegeneration with ataxia and late-onset optic atrophy [OMIM# 619259] disease entity is curated here and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two unique missense variants [NM_004168.4, c.1351C>T (p.Arg451Cys) and c.1984C>T (p.Arg662Cys)] identified in three unrelated cases from three publications (PMIDs: 10976639, 27683074, 33471299). Of note, the c.1351C>T (p.Arg451Cys) variant has been reported in two unrelated cases with overlapping phenotypes and functional validation supports a deleterious effect (PMIDs: 10976639, 27683074). Clinical features in affected individuals include myopathy, ataxia, developmental delay, optic atrophy, and cardiomyopathy. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416) and yeast models (PMIDs: 1511876, 28724664, 39321216). Of note, this Expert Panel elected to score experimental evidence conservatively as no other complex II genes have been associated with autosomal dominant primary mitochondrial disease and because *SDHA* has a Definitive association with a separate phenotypic entity, autosomal dominant hereditary paraganglioma and pheochromocytomas. The mechanism of disease is unclear however further studies are needed as it is unclear why some autosomal dominant *SDHA* variants are associated with a predisposition to hereditary cancer syndromes while others are associated with a primary mitochondrial disease. In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 11, 2025 (SOP Version 11).

gastrointestinal stromal tumorSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011719

Submitter: Orphanet

pheochromocytoma/paraganglioma syndrome 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013602

Submitter: PanelApp Australia

pheochromocytoma/paraganglioma syndrome 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013602

Submitter: G2P

mitochondrial complex II deficiency, nuclear type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100294

Submitter: G2P

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SDHA* and autosomal recessive *SDHA*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 17, 2024. The *SDHA* gene encodes the flavoprotein subunit of complex II (succinate dehydrogenase), which plays an essential role in both the citric acid cycle and in the electron transport chain by catalyzing the oxidation of succinate to fumarate. The *SDHA* gene was first reported in relation to autosomal recessive *SDHA*-related primary mitochondrial disease in 1995 (PMID: 7550341). *SDHA* has been associated with four disease entities to date; autosomal recessive cardiomyopathy, dilated, 1GG [OMIM# 613642], autosomal recessive mitochondrial complex II deficiency, nuclear type 1 [OMIM# 252011], autosomal dominant neurodegeneration with ataxia and late-onset optic atrophy [OMIM# 619259], and autosomal dominant pheochromocytoma/paraganglioma syndrome 5 [OMIM# 614165]. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, this Expert Panel found a difference in molecular mechanism, inheritance pattern, and phenotypic variability among several of these entities. Therefore, the two autosomal recessive disease entities (autosomal recessive cardiomyopathy, dilated, 1GG [OMIM# 613642] and autosomal recessive mitochondrial complex II deficiency, nuclear type 1 [OMIM# 252011]) have been lumped into one disease entity and renamed autosomal recessive *SDHA*-related primary mitochondrial disease. Of note, *SDHA* was first curated by this Expert Panel for its association with autosomal recessive Leigh syndrome spectrum (LSS) on May 13, 2019 (SOP v6), with a final classification of Moderate. This current curation for the association with autosomal recessive *SDHA*-related primary mitochondrial disease includes cases with LSS. The autosomal dominant disease entities (autosomal dominant neurodegeneration with ataxia and late-onset optic atrophy [OMIM# 619259], and autosomal dominant pheochromocytoma/paraganglioma syndrome 5 [OMIM# 614165]) have been split and curated separately. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 10 unique variants (six missense, two nonsense, one in-frame deletion, one intronic) identified in nine unrelated cases from seven publications (PMIDs: 7550341, 12794685, 16798039, 20551992, 16361598, 24781757, PMID: 33960148), although more affected individuals have been reported in the medical literature. Disease onset is typically early in life. Clinical features in affected individuals include LSS, developmental delay and regression, myopathy, seizures, ataxia, tremor, dystonia, spasticity, cardiac arrhythmia, cardiomyopathy, anemia, failure to thrive, hepatosplenomegaly, metabolic acidosis, and Complex II deficiency. Brain imaging can be normal, consistent with LSS, or show a leukodystrophy. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration in patient cells (PMID: 10746566), yeast studies (PMIDs:9730279, 1511876), and an embryonic lethal mouse knockout (PMID: 27626380). In summary, there is definitive evidence to support the relationship between *SDHA* and autosomal recessive *SDHA*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 17, 2024 (SOP Version 10).

pheochromocytoma/paraganglioma syndrome 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013602

Submitter: Ambry Genetics

pheochromocytoma/paraganglioma syndrome 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013602

Submitter: Illumina

dilated cardiomyopathy 1GGLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013339

Submitter: Ambry Genetics

neurodegeneration with ataxia and late-onset optic atrophyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0031006

Submitter: Ambry Genetics

hereditary pheochromocytoma-paragangliomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: ClinGen

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] are associated with an increased risk of multiple paragangliomas and pheochromocytomas tumors within multiple organ systems transmitted in autosomal dominant inheritance. The molecular mechanism is loss of function in one of the 4 genes comprising the succinate dehydrogenase and SDHAF gene for flavination of SDHA, and stabilization of the SDH complex. This is a curation for SDHA and SDHA associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) with autosomal dominant inheritance (Paraganglioma 5, MIM: 614165). The autosomal recessive inherited Leigh syndrome (MIM: 256000), Cardiomyopathy, dilated, 1GG (MIM: 613642) and Mitochondrial Respiratory Chain Complex II deficiency (MIM: 252011) will be curated separately. SDHA encodes the flavoprotein subunit of the SDH-complex (succinate dehydrogenase). SDHA was first reported in relation to PGL/PCC in 1995 [Bourgeron et al., PMID: 7550341]. Germline loss-of-function mutations of SDHA gene have been described in only 3-7% of the patients with PGL/PCCs, in which most pathogenic variants are associated with very low disease penetrance, ranging from 0.1-4.9% [PMID: 29978154]. An initiation codon, two missense, four nonsense and two small deletion variants are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence. Absence of SDHA staining specifically associated with SDHA germline mutation in PGL/PCC tumors was demonstrated in 6 cases with 6 germline variants [PMID: 23282968]. Yeast models with null Sdh1 and Arg582Trp Sdh1 mutants showed loss of SDH1 due to instability of the mutant protein. SDHB protein, the catalytic component, is lost in the SDHA mutant patient’s fresh adrenal paraganglioma tumor. WT yeast SDH1 can rescue the deficient growth of null Sdh1 mutant on minimal glycerol/ethanol but the yeast Arg582Trp Sdh1 mutant can not [PMID: 20484225]. In summary, the SDHA gene is definitely associated with autosomal dominant HPGL/PCC with low penetrance. This has been repeatedly demonstrated in both the genetic, and experimental, biochemical and functional studies, and has been upheld over time.

mitochondrial complex II deficiency, nuclear type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100294

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: Ambry Genetics

mitochondrial complex II deficiency, nuclear type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100294

Submitter: Labcorp Genetics (formerly Invitae)

pheochromocytoma/paraganglioma syndrome 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013602

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex II deficiency, nuclear type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100294

Submitter: Ambry Genetics

neurodegeneration with ataxia and late-onset optic atrophySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0031006

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic; Oncologic

Intervention: Biochemical; Cardiovascular; Gastrointestinal; Oncologic

Rationale: For conditions that involve increased risk of neoplasms, awareness and surveillance may allow early diagnosis and treatment (eg, via surgical management), which may improve outcomes; In conditions such as Cardiomyopathy, dilated, Neurodegeneration with ataxia and late-onset optic atrophy; and Mitochondrial respiratory chain complex II deficiency, nuclear type 1, recognition of cardiovascular disease may allow early medical management, which may be helpful to help decrease morbidity; In Mitochondrial respiratory chain complex II deficiency, medical treatment (eg, with riboflavin, ubiquinol) may be beneficial, and individuals may have cardiac involvement such that surveillance may be beneficial

Refs: 7550341; 8967754; 10746566; 10976639; 12794685; 16737791; 16798039; 20484225; 20551992; 21505157; 22972948; 23322652; 27683074

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SDHA variants in ClinVar

37 Conditions Cataloged

Pheochromocytoma/paraganglioma syndrome 5Total: 2710

Mitochondrial complex II deficiency, nuclear type 1Total: 2573

Hereditary cancer-predisposing syndromeTotal: 2001

not providedTotal: 442

Dilated cardiomyopathy 1GGTotal: 325

Neurodegeneration with ataxia and late-onset optic atrophyTotal: 124

not specifiedTotal: 100

SDHA-related disorderTotal: 90

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004168.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	3 clinvar	2 clinvar	15 clinvar	680 clinvar	40 clinvar	740
missense	8 clinvar	52 clinvar	1480 clinvar	93 clinvar	2 clinvar	1635
nonsense	64 clinvar	13 clinvar	1 clinvar			78
start loss	7 clinvar	4 clinvar				11
frameshift	123 clinvar	41 clinvar	13 clinvar			177
splice donor/acceptor (+/-2bp)	3 clinvar	79 clinvar	9 clinvar	2 clinvar		93
Total	208	191	1518	775	42	2734

Highest pathogenic variant AF is 0.0004034707

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 129 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004168.4	RefSeq	NP_004159.2	15	MANE Select
ENST00000264932.11	Ensembl	ENSP00000264932.6	15	MANE Select
NM_001294332.2	RefSeq	NP_001281261.1	14	Standard
NM_001330758.2	RefSeq	NP_001317687.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Citrate cycle (TCA cycle) - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

tricarboxylic acid cycle
succinate metabolic process
mitochondrial electron transport, succinate to ubiquinone
nervous system development
respiratory electron transport chain

Molecular Function

succinate dehydrogenase activity
protein binding
succinate dehydrogenase (ubiquinone) activity
electron transfer activity
flavin adenine dinucleotide binding

Cellular Component

nucleolus
mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex II, succinate dehydrogenase complex (ubiquinone)
myelin sheath

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264932
Coding exons: 15
Length: 38460
Individuals with no LoFs: 125631
Homozygous LoFs: 0
Heterozygous LoFs: 117
Defined: 125748
p: 0.000465

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.745	346	387	0.893	0.0000260	4262
Missense (PolyPhen)		139	179.81	0.77303		1899
Synonymous	-1.41	184	161	1.14	0.0000122	1339
Loss of Function	2.22	21	35.2	0.596	0.00000219	385

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00075	0.00075	rare
South Asian	0.00033	0.00029	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (PubMed:24781757). Can act as a tumor suppressor (PubMed:20484225). {ECO:0000269|PubMed:20484225, ECO:0000305|PubMed:24781757}.;
Disease: DISEASE: Mitochondrial complex II deficiency (MT-C2D) [MIM:252011]: A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. Note=The disease is caused by mutations affecting the gene represented in this entry. {ECO:0000269|PubMed:12794685}.; DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:10746566, ECO:0000269|PubMed:24781757, ECO:0000269|PubMed:7550341}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1GG (CMD1GG) [MIM:613642]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:20551992}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Paragangliomas 5 (PGL5) [MIM:614165]: A neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion. Paragangliomas can develop at various body sites, including the head, neck, thorax and abdomen. Most commonly, they are located in the head and neck region, specifically at the carotid bifurcation, the jugular foramen, the vagal nerve, and in the middle ear. {ECO:0000269|PubMed:20484225}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.432
RVIS EVS: -0.86
RVIS percentile EVS: 10.95

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.983

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium