Is SMARCA4 p.Lys970Arg (c.2909A>G) pathogenic?

SMARCA4 p.Lys970Arg (c.2909A>G) is classified Uncertain significance in SMARCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-02). AlphaMissense: likely pathogenic (0.6959); Very rare (popmax 8.48e-05%, nfe); Associated with rhabdoid tumor predisposition syndrome 2.

What condition is associated with SMARCA4 p.Lys970Arg (c.2909A>G)?

SMARCA4 p.Lys970Arg (c.2909A>G) is associated with rhabdoid tumor predisposition syndrome 2 (ClinVar).

How common is SMARCA4 p.Lys970Arg (c.2909A>G) in the general population?

SMARCA4 p.Lys970Arg (c.2909A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Rhabdoid tumor predisposition syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SMARCA4 p.Lys970Arg (c.2909A>G)?

AlphaMissense predicts likely pathogenic (score 0.6959) — an in-silico prediction, not a clinical call.

SMARCA4 p.Lys970Arg

c.2909A>G · VCV3636872

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

rhabdoid tumor predisposition syndrome 2

Computational evidence

Protein change
AlphaMissense	0.6959	likely pathogenic
REVEL	0.671	pathogenic-leaning
SaProt	LLR -11.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.19	constrained · MANE · 9,117 bp · p 4.1e-58 · regional, not allelic
Overall
CADD	28.6	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,834 alleles

Overall 6.2e-05% 1/1,613,694 alleles · very rare exomes 1/1,461,364 · 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: SMARCA4
Protein: p.Lys970Arg
Coding: c.2909A>G
MANE Select: NM_003072
Type: single nucleotide variant
Location: chr19:11023567 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 970: an α-helix

Full SMARCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

rhabdoid tumor predisposition syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rhabdoid tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

SMARCA4 c.1943+1G>A Likely pathogenic ★★ same condition
SMARCA4 c.2274+1G>T Likely pathogenic ★★ same condition
SMARCA4 c.2438+1G>A Pathogenic/Likely pathogenic ★★ same condition
SMARCA4 c.3216-1G>C Likely pathogenic ★★ same condition
SMARCA4 c.3216-2A>G Likely pathogenic ★★ same condition
SMARCA4 c.3546+1G>A Likely pathogenic ★★ same condition
SMARCA4 c.3774+2T>A Likely pathogenic ★★ same condition
SMARCA4 c.3951+2T>C 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/smarca4-p-lys970arg (accessed [today's date]).

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