Is SMARCC2 p.Arg466Pro (c.1397G>C) pathogenic?

SMARCC2 p.Arg466Pro (c.1397G>C) is classified Uncertain significance in SMARCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-04). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with Coffin-Siris syndrome 1.

What condition is associated with SMARCC2 p.Arg466Pro (c.1397G>C)?

SMARCC2 p.Arg466Pro (c.1397G>C) is associated with Coffin-Siris syndrome 1 (ClinVar).

How common is SMARCC2 p.Arg466Pro (c.1397G>C) in the general population?

SMARCC2 p.Arg466Pro (c.1397G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMARCC2 p.Arg466Pro (c.1397G>C)?

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

SMARCC2 p.Arg466Pro

c.1397G>C · VCV4533304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Coffin-Siris syndrome 1

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic · top 9% in SMARCC2
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -10.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 4,679 bp · p 4.6e-13 · regional, not allelic
Overall
CADD	34.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMARCC2
Protein: p.Arg466Pro
Coding: c.1397G>C
MANE Select: NM_001330288
Type: single nucleotide variant
Location: chr12:56174750 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 9 PDB
Residue 466: a UniProt-annotated variant site (in css8); the swirm domain; an α-helix

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

Disease context

Coffin-Siris syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMARCC2 p.Arg466Ter Likely pathogenic ★ same residue
SMARCC2 c.231+1G>T Likely pathogenic ★ same condition
SMARCC2 c.2549-2A>G Likely pathogenic ★ same condition
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

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-arg466pro (accessed [today's date]).

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