Is SMARCC2 p.Pro1163Gln (c.3488C>A) pathogenic?

SMARCC2 p.Pro1163Gln (c.3488C>A) is classified Uncertain significance in SMARCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-24). AlphaMissense: likely benign (0.0938); Very rare (popmax 0.00167%, amr); Associated with Coffin-Siris syndrome 8.

What condition is associated with SMARCC2 p.Pro1163Gln (c.3488C>A)?

SMARCC2 p.Pro1163Gln (c.3488C>A) is associated with Coffin-Siris syndrome 8 (ClinVar).

How common is SMARCC2 p.Pro1163Gln (c.3488C>A) in the general population?

SMARCC2 p.Pro1163Gln (c.3488C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SMARCC2 p.Pro1163Gln (c.3488C>A)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

SMARCC2 p.Pro1163Gln

c.3488C>A · VCV3892518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Coffin-Siris syndrome 8

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -9.25	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 6.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,903 bp · p 0.032 · regional, not allelic
Overall
CADD	25.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1132Q vs ClinVar P1163Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,024 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000434% 7/1,614,156 alleles · very rare exomes 6/1,461,820 · genomes 1/152,336 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,024
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asian	0.0011%	91,082
European (non-Finnish)	0.000339%	295,004

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.Pro1163Gln
Coding: c.3488C>A
MANE Select: NM_001330288
Type: single nucleotide variant
Location: chr12:56164476 (GRCh38)
Gene constraint: LOEUF 0.167 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 9 PDB
Residue 1132 UniProt numbering: a UniProt-annotated variant site (in css8)

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 p.Pro1163Ser Uncertain significance ★ ⚠ same residue
SMARCC2 p.Pro1163Ala Likely benign same residue
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

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-pro1163gln (accessed [today's date]).

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