Is SMARCC2 p.Ser776Phe (c.2327C>T) pathogenic?

SMARCC2 p.Ser776Phe (c.2327C>T) is classified Likely benign in SMARCC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.2115); Rare (popmax 0.247%, sas).

How common is SMARCC2 p.Ser776Phe (c.2327C>T) in the general population?

SMARCC2 p.Ser776Phe (c.2327C>T) is rare (popmax 0.247%, sas) (gnomAD).

What do computational predictors say about SMARCC2 p.Ser776Phe (c.2327C>T)?

AlphaMissense predicts likely benign (score 0.2115) — an in-silico prediction, not a clinical call.

SMARCC2 p.Ser776Phe

c.2327C>T · rs187335194 · VCV3035861

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2115 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.247%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2115	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -9.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 1,806 bp · p 1.6e-06 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S745F vs ClinVar S776F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.247% South Asian · 225/91,088 alleles

Filtering AF 0.221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.21%

Overall 0.0215% 347/1,614,234 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.247%	405
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00898%	11,132
African / African-American	0.00266%	37,534

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.Ser776Phe
Coding: c.2327C>T
MANE Select: NM_001330288
dbSNP: rs187335194
Type: single nucleotide variant
Location: chr12:56171291 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 9 PDB
Residue 776: a UniProt-annotated variant site (in css8); the 'disordered' region

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

Similar variants

SMARCC2 c.1311-3C>G Pathogenic/Likely pathogenic ★★ same type
SMARCC2 c.1926+1G>A Pathogenic/Likely pathogenic ★★ same type
SMARCC2 c.1926+1G>T Pathogenic/Likely pathogenic ★★ same type
SMARCC2 c.1926+2T>C Pathogenic/Likely pathogenic ★★ same type
SMARCC2 p.Arg116His Likely pathogenic ★★ same type
SMARCC2 p.Arg192Ter Pathogenic/Likely pathogenic ★★ same type
SMARCC2 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same type
SMARCC2 p.Arg474Ter Pathogenic/Likely pathogenic ★★ same type

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-ser776phe (accessed [today's date]).

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