Is SMARCC2 p.Pro323Ser (c.967C>T) pathogenic?

SMARCC2 p.Pro323Ser (c.967C>T) is classified Uncertain significance in SMARCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.2173); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with SMARCC2 p.Pro323Ser (c.967C>T)?

SMARCC2 p.Pro323Ser (c.967C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SMARCC2 p.Pro323Ser (c.967C>T) in the general population?

SMARCC2 p.Pro323Ser (c.967C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about SMARCC2 p.Pro323Ser (c.967C>T)?

AlphaMissense predicts likely benign (score 0.2173) — an in-silico prediction, not a clinical call.

SMARCC2 p.Pro323Ser

c.967C>T · rs748303040 · VCV1311949

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2173 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2173	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -5.65	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 3,062 bp · p 0.22 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,748 alleles

Overall 0.000124% 2/1,612,502 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,748
European (non-Finnish)	8.48e-05%	1,179,549

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.Pro323Ser
Coding: c.967C>T
MANE Select: NM_001330288
dbSNP: rs748303040
Type: single nucleotide variant
Location: chr12:56181091 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 9 PDB
Residue 323: a UniProt-annotated variant site (in css8); the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMARCC2 p.Gln1054Ter Pathogenic ★★ same condition
SMARCC2 p.Ala1198Thr Uncertain significance ★★ ⚠ same condition
SMARCC2 p.Arg288Gln Uncertain significance ★★ ⚠ same condition
SMARCC2 p.Asn351Ser Uncertain significance ★★ ⚠ same condition
SMARCC2 p.Gln1043His Uncertain significance ★★ ⚠ same condition
SMARCC2 p.Ile159Val Uncertain significance ★★ ⚠ same condition
SMARCC2 p.Pro1121Ser Uncertain significance ★★ ⚠ same condition
SMARCC2 p.Ser1031Asn Uncertain significance ★★ ⚠ 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-pro323ser (accessed [today's date]).

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