NDUFAF8

protein-coding

NADH:ubiquinone oxidoreductase complex assembly factor 8, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrial matrix. Implicated in nuclear type mitochondrial complex I deficiency 34. [provided by Alliance of Genome Resources, Jul 2025]

Previous symbols:

C17orf89

MANE transcript

NM_001086521.2

Inheritance

ClinVar variants

P:5U:6B:3

Top phenotype

Mitochondrial complex I deficiency, nuclear type 34

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr17:81,239,305-81,241,310

External References & Databases

Ensembl (ENSG00000224877)

Transcript & Mutation Effects

hg38 • Region Span ~2.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 34MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032910

Submitter: Ambry Genetics

mitochondrial complex I deficiency, nuclear type 34STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032910

Submitter: G2P

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFAF8 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of January 13, 2020. The NDUFAF8 gene encodes NADH:ubiquinone oxidoreductase (complex I) assembly factor 8. The NDUFAF8 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2020 (PMID: 31866046). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants identified in three unrelated cases from one publication (PMID: 31866046). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in non-patient cells, functional alteration in patient cells, rescue in a cell culture model, and rescue in patient cells (PMIDs: 27499296, 31866046). In summary, there is moderate 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 13, 2020 (SOP Version 7).

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Leigh syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: PanelApp Australia

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFAF8* and *NDUFAF8*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 4, 2024. The *NDUFAF8* gene encodes NADH:ubiquinone oxidoreductase (complex I) assembly factor 8. The *NDUFAF8* gene was first reported in relation to autosomal recessive *NDUFAF8*-related primary mitochondrial disease in 2020 (PMID: 31866046). *NDUFAF8* has been associated with one disease entity to date; mitochondrial complex I deficiency, nuclear type 34 [OMIM# 618776]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFAF8*-related primary mitochondrial disease. Of note, *NDUFAF8* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on January 13, 2020 (SOP v7), with a final classification of Moderate. This current curation for the association with *NDUFAF8*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants (one missense, one frameshift, one initiation codon, one intronic) identified in three unrelated cases from one publication (PMID: 31866046). Disease onset is early in life. Clinical features in affected individuals include LSS, developmental delay and regression, seizures, feeding difficulty, optic atrophy, hypertensive crises, respiratory failure, intrauterine growth restriction, metabolic acidosis, and elevated lactate. Complex I deficiency was noted in skeletal muscle and skin fibroblasts from affected individuals. 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: 31866046), functional alteration in patient cells (PMID: 31866046), functional alteration in non-patient cells (PMID: 27499296), rescue in patient cells (PMID: 31866046), and rescue in non-patient cells (PMID: 27499296). In summary, there is moderate evidence to support the relationship between *NDUFAF8* and autosomal recessive *NDUFAF8*-related primary mitochondrial disease. 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 November 4, 2024 (SOP Version 11).

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 34AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

Refs: 31866046

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFAF8 variants in ClinVar

5 Conditions Cataloged

Mitochondrial complex I deficiency, nuclear type 34Total: 5

Inborn genetic diseasesTotal: 5

not providedTotal: 4

Mitochondrial diseaseTotal: 4

NDUFAF8-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001086521.2. 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				1 clinvar		1
missense		1 clinvar	6 clinvar	2 clinvar		9
nonsense						0
start loss	2 clinvar					2
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)						0
Total	4	1	6	3	0	14

Highest pathogenic variant AF is 0.0007287788

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001086521.2	RefSeq	NP_001079990.1	3	MANE Select
ENST00000431388.3	Ensembl	ENSP00000400184.2	3	MANE Select
NM_001353402.1	RefSeq	NP_001340331.1	3	Standard
NM_001353403.1	RefSeq	NP_001340332.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrial respiratory chain complex I assembly

Molecular Function

protein binding

Cellular Component

mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000431388
Coding exons: 3
Length: 2043
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.395	21	26.7	0.785	0.00000134	451
Missense (PolyPhen)		6	6.8578	0.87492		116
Synonymous	0.241	11	12.1	0.912	6.43e-7	150
Loss of Function	0.626	1	1.94	0.515	8.30e-8	36

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) (PubMed:27499296). Required to stabilize NDUFAF5 (PubMed:27499296). {ECO:0000269|PubMed:27499296}.;

Essentials

Essential (gene trap): N