Is SMARCC2 p.Val3Ala (c.8T>C) pathogenic?

SMARCC2 p.Val3Ala (c.8T>C) is classified Uncertain significance in SMARCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.5836); Ultra-rare (popmax 0.0194%, nfe); Associated with Coffin-Siris syndrome 8.

What condition is associated with SMARCC2 p.Val3Ala (c.8T>C)?

SMARCC2 p.Val3Ala (c.8T>C) is associated with Coffin-Siris syndrome 8 (ClinVar).

How common is SMARCC2 p.Val3Ala (c.8T>C) in the general population?

SMARCC2 p.Val3Ala (c.8T>C) is ultra-rare (popmax 0.0194%, nfe) (gnomAD).

What do computational predictors say about SMARCC2 p.Val3Ala (c.8T>C)?

AlphaMissense predicts likely pathogenic (score 0.5836) — an in-silico prediction, not a clinical call.

SMARCC2 p.Val3Ala

c.8T>C · rs141878487 · VCV3166337

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0194%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Coffin-Siris syndrome 8

Computational evidence

Protein change
AlphaMissense	0.5836	likely pathogenic
REVEL	0.024	moderately benign-leaning
SaProt	LLR -3.95	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP -0.19, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 2,158 bp · p 0.74 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0194% European (non-Finnish) · 215/1,108,238 alleles

Filtering AF 0.0173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0164%

Overall 0.0157% 234/1,487,662 alleles · ultra-rare exomes 215/1,337,322 · genomes 19/150,340 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0288%	3,471
European (non-Finnish)grpmax	0.0194%	5,155
African / African-American	0.00434%	23,057

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SMARCC2
Protein: p.Val3Ala
Coding: c.8T>C
MANE Select: NM_001330288
dbSNP: rs141878487
Type: single nucleotide variant
Location: chr12:56189454 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 9 PDB
Residue 3: the 'marr-like, brct and chromo domains module' region

Full SMARCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Coffin-Siris syndrome 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMARCC2 c.1311-3C>G Pathogenic/Likely pathogenic ★★ same condition
SMARCC2 c.1926+1G>A Pathogenic/Likely pathogenic ★★ same condition
SMARCC2 c.1926+1G>T Pathogenic/Likely pathogenic ★★ same condition
SMARCC2 c.1926+2T>C Pathogenic/Likely pathogenic ★★ same condition
SMARCC2 p.Arg192Ter Pathogenic/Likely pathogenic ★★ same condition
SMARCC2 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same condition
SMARCC2 p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
SMARCC2 p.Glu924Gly Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/smarcc2-p-val3ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown