SMG8

protein-coding

SMG8 nonsense mediated mRNA decay factor, the group of SMG1 complex

Gene summary

Involved in nuclear-transcribed mRNA catabolic process, nonsense-mediated decay and regulation of protein kinase activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Jul 2025]

Previous symbols:

C17orf71

MANE transcript

NM_018149.7

Inheritance

ClinVar variants

P:14U:126B:21

Top phenotype

Alzahrani-Kuwahara syndrome

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr17:59,209,400-59,215,239

External References & Databases

Ensembl (ENSG00000167447)

Transcript & Mutation Effects

hg38 • Region Span ~5.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Alzahrani-Kuwahara syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859136

Submitter: G2P

Alzahrani-Kuwahara syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859136

Submitter: Ambry Genetics

Alzahrani-Kuwahara syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859136

Submitter: Labcorp Genetics (formerly Invitae)

Alzahrani-Kuwahara syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859136

Submitter: PanelApp Australia

Alzahrani-Kuwahara syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0859136

Submitter: ClinGen

The SMG8 (suppressor with morphogenetic effects on genitalia 8) gene is located on chromosome 17 (17q22) and encodes a protein that serves as a nonsense mediated mRNA decay factor, binding SMG9 to facilitate the recruitment of SMG1 to the SURF complex (Yamashita et al., 2009, PMID:19417104). SMG8 was first reported in relation to autosomal recessive Alzahrani-Kuwahara syndrome (ALKUS) in 2020 (Alzahrani et. al., PMID:33242396). The ALKUS clinical presentation is characterized by early onset severe global developmental delay, intellectual disability, microcephaly, facial dysmorphism, variable congenital heart malformations, and variable eye malformations (OMIM: 613175). Genetic and clinical evidence reviewed in the curation of this gene-disease relationship included four Middle Eastern probands from consanguineous families with four unique homozygous variants. Each proband had at least one affected sibling with the same genotype and phenotype (Alzahrani et al., 2020, PMID:33242396, LOD score 3). A fifth affected Middle Eastern proband with a fifth homozygous variant was published separately (Abdel-Salam et al., 2021, PMID: 34761517), and a sixth proband from a non-consanguineous Brazilian family was found to have two additional previously unreported variants (1 nonsense, 1 frameshift) in trans based on parental testing (Fernandes et al., 2023, PMID: 37194129). The molecular mechanism of disease appears to be biallelic loss of function (5 out of 7 of the published variants are protein-truncating variants and the two missense variants are predicted to disrupt the binding of SMG8 to its partner SMG9). This gene-disease relationship is also supported by protein interactions, functional alterations, and rescue in a cell culture model. SMG9 variants cause a different syndrome (Shaheen et al., 2016, PMID: 27018474, MONDO:0014833) with a similar clinical presentation to that observed in ALKUS patients. SMG8 and SMG9 interact and the loss of the SMG8 C-terminus results in loss of SMG1 inhibition, independently disrupting nonsense-mediated decay (Zhu et al., 2019, PMID: 31729466). Depletion of SMG8 in Ullrich’s disease patient fibroblasts rescued an NMD-exacerbated mutant phenotype (Usuki et. al. 2013, PMID: 23983263). In summary, there is definitive genetic and experimental evidence supporting the relationship between SMG8 and autosomal recessive ALKUS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This definitive classification was approved by the ClinGen Syndromic Disorders GCEP in the meeting on November 1, 2023 (SOP Version 10).

Clinical Genomic Database (CGD)

Alzahrani-Kuwahara syndromeAR

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 33242396

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMG8 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 108

not providedTotal: 38

Alzahrani-Kuwahara syndromeTotal: 16

SMG8-related disorderTotal: 7

not specifiedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018149.7. 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			2 clinvar	15 clinvar	1 clinvar	18
missense	1 clinvar		116 clinvar	4 clinvar	1 clinvar	122
nonsense	4 clinvar	1 clinvar	2 clinvar			7
start loss						0
frameshift	4 clinvar	4 clinvar	6 clinvar			14
splice donor/acceptor (+/-2bp)						0
Total	9	5	126	19	2	161

Highest pathogenic variant AF is 0.000029738267

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018149.7	RefSeq	NP_060619.4	4	MANE Select
ENST00000300917.10	Ensembl	ENSP00000300917.4	4	MANE Select
ENST00000543872.6	Ensembl	ENSP00000438748.2	4	Standard
ENST00000543872.7	Ensembl	ENSP00000438748.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of RNA
Nonsense-Mediated Decay (NMD)
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

Biological Process

nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
regulation of protein kinase activity

Molecular Function

protein binding

Cellular Component

cellular_component
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000543872
Coding exons: 4
Length: 5848
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125747
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.73	416	528	0.788	0.0000261	6446
Missense (PolyPhen)		114	182.59	0.62433		2244
Synonymous	0.655	185	197	0.941	0.00000968	2009
Loss of Function	4.23	12	41.3	0.290	0.00000277	427

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00024	0.00020	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Is recruited by release factors to stalled ribosomes together with SMG1 and SMG9 (forming the SMG1C protein kinase complex) and, in the SMG1C complex, is required to mediate the recruitment of SMG1 to the ribosome:SURF complex and to suppress SMG1 kinase activity until the ribosome:SURF complex locates the exon junction complex (EJC). Acts as a regulator of kinase activity. {ECO:0000269|PubMed:19417104}.;

Intolerance Scores

RVIS EVS: -0.86
RVIS percentile EVS: 10.92

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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