Is SMARCA2 p.Ala409Val (c.1226C>T) pathogenic?

SMARCA2 p.Ala409Val (c.1226C>T) is classified Uncertain significance in SMARCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: likely pathogenic (0.7753); Very rare (popmax 8.47e-05%, nfe).

How common is SMARCA2 p.Ala409Val (c.1226C>T) in the general population?

SMARCA2 p.Ala409Val (c.1226C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SMARCA2 p.Ala409Val (c.1226C>T)?

AlphaMissense predicts likely pathogenic (score 0.7753) — an in-silico prediction, not a clinical call.

SMARCA2 p.Ala409Val

c.1226C>T · VCV4902346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7753 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7753	likely pathogenic
REVEL	0.285	benign-leaning
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 11 kb · p 7.4e-11 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,192 alleles · very rare exomes 1/1,461,862 · genomes 0/152,330 · joint denominator

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: SMARCA2
Protein: p.Ala409Val
Coding: c.1226C>T
MANE Select: NM_003070
Type: single nucleotide variant
Location: chr9:2056724 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.06 · 32 PDB

Full SMARCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMARCA2 p.Ala409Gly Uncertain significance ★ ⚠ same residue
SMARCA2 p.Ala1138Pro Pathogenic/Likely pathogenic ★★ same type
SMARCA2 p.Ala1160Gly Pathogenic ★★ same type
SMARCA2 p.Ala1201Glu Pathogenic/Likely pathogenic ★★ same type
SMARCA2 p.Ala1201Val Pathogenic/Likely pathogenic ★★ same type
SMARCA2 p.Arg1105Cys Pathogenic ★★ same type
SMARCA2 p.Arg1105His Pathogenic ★★ same type
SMARCA2 p.Arg1105Pro 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/smarca2-p-ala409val (accessed [today's date]).

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