Is SMARCC2 p.Leu922Pro (c.2765T>C) pathogenic?

SMARCC2 p.Leu922Pro (c.2765T>C) is classified Uncertain significance in SMARCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-01). AlphaMissense: likely pathogenic (1); Very rare (popmax 8.47e-05%, nfe).

How common is SMARCC2 p.Leu922Pro (c.2765T>C) in the general population?

SMARCC2 p.Leu922Pro (c.2765T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SMARCC2 p.Leu922Pro (c.2765T>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

SMARCC2 p.Leu922Pro

c.2765T>C · rs1565896474 · VCV2570834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic · top 9% in SMARCC2
REVEL	0.724	pathogenic-leaning
SaProt	LLR -15.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 4,003 bp · p 1.4e-13 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L891P vs ClinVar L922P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 6.84e-05% 1/1,461,892 alleles · very rare

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.Leu922Pro
Coding: c.2765T>C
MANE Select: NM_001330288
dbSNP: rs1565896474
Type: single nucleotide variant
Location: chr12:56168145 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 9 PDB
Residue 922: a UniProt-annotated variant site (in css8); an α-helix

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-leu922pro (accessed [today's date]).

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