SMCR8

Chr 17

SMCR8-C9orf72 complex subunit

Also known as: DENND8A

NCBI Gene: 140775ENSG00000176994UniProt: Q8TEV9

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]

0
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
0
Active trials
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.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.65LOEUF
pLI 0.002
Z-score 2.84
OE 0.37 (0.23–0.65)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-1.03Z-score
OE missense 1.13 (1.05–1.21)
574 obs / 508.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.23–0.65)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.13 (1.05–1.21)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.28
0≤1.21.6
LoF obs/exp: 9 / 24.0Missense obs/exp: 574 / 508.9Syn Z: -3.23

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

SMCR8 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cellular and physiological functions of C9ORF72 and implications for ALS/FTD.
Pang W et al.·J Neurochem
2021Review
C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease.
Goodier JL et al.·Acta Neuropathol Commun
2020
Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator.
Jung J et al.·Elife
2017
Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech.
Peter B et al.·PLoS One
2016
Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers.
Dickson DW et al.·Acta Neuropathol Commun
2019
Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers.
Jackson JL et al.·Mol Neurodegener
2020Cohort
Unraveling the molecular mechanisms of ALS: a network biology and structural modeling approach of investigating the impact of C9orf72 mutations.
Alzahrani AK et al.·J Biomol Struct Dyn
2026Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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External Resources

Links to major genomics databases and tools