SMCR8

Chr 17

SMCR8-C9orf72 complex subunit

Also known as: DENND8A

NCBI Gene: 140775 ENSG00000176994 OMIM: 617074

SMCR8 encodes a component of the C9orf72-SMCR8 complex that functions as a guanine nucleotide exchange factor and regulates autophagy by promoting RAB GTPase activation and inhibiting ULK1 kinase activity. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability, developmental delay, and seizures. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.654), suggesting some tolerance for such mutations.

OMIM ResearchSummary from RefSeq, UniProt

Enables GTPase activator activity; protein kinase binding activity; and protein kinase inhibitor activity. Contributes to guanyl-nucleotide exchange factor activity. Involved in negative regulation of gene expression; regulation of TOR signaling; and regulation of macroautophagy. Located in Atg1/ULK1 kinase complex; chromatin; and nucleoplasm. Part of guanyl-nucleotide exchange factor complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOEUF 0.65

Clinical Summary— SMCR8

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

141 VUS of 154 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.002

Z-score 2.84

OE 0.37 (0.23–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.03Z-score

OE missense 1.13 (1.05–1.21)

574 obs / 508.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.37 (0.23–0.65)

0≤0.351.4

Missense OE?1.13 (1.05–1.21)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 9 / 24.0Missense obs/exp: 574 / 508.9Syn Z: -3.23

ClinVar Variant Classifications

154 submitted variants in ClinVar

ClinVar

Classification Summary

VUS141

Likely Benign4

Benign1

141

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	141	0	141
Likely Benign	2	2	4
Benign	1	0	1
Total	144	2	146

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

113 pathogenic / likely-pathogenic (of 118) ClinVar copy-number / structural variants overlap SMCR8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →