Is SMARCA4 p.Pro273Ser (c.817C>T) pathogenic?

SMARCA4 p.Pro273Ser (c.817C>T) is classified Conflicting classifications of pathogenicity in SMARCA4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-04). AlphaMissense: likely benign (0.0765); Very rare (popmax 8.48e-05%, nfe); Associated with rhabdoid tumor predisposition syndrome 2.

What condition is associated with SMARCA4 p.Pro273Ser (c.817C>T)?

SMARCA4 p.Pro273Ser (c.817C>T) is associated with rhabdoid tumor predisposition syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is SMARCA4 p.Pro273Ser (c.817C>T) in the general population?

SMARCA4 p.Pro273Ser (c.817C>T) 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.Pro273Ser (c.817C>T)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

SMARCA4 p.Pro273Ser

c.817C>T · rs1472583838 · VCV827491

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

rhabdoid tumor predisposition syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 2,911 bp · p 0.24 · regional, not allelic
Overall
CADD	24.4	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 8.48e-05% European (non-Finnish) · 1/1,179,862 alleles

Overall 0.000186% 3/1,609,588 alleles · very rare exomes 2/1,457,396 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00335%	29,889
European (non-Finnish)grpmax	8.48e-05%	1,179,862

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro273Ser
Coding: c.817C>T
MANE Select: NM_003072
dbSNP: rs1472583838
Type: single nucleotide variant
Location: chr19:10986961 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 273: the 'necessary for interaction with ss18l1/crest' region; the 'disordered' region

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

Also linked: hereditary neoplastic syndrome

For Rhabdoid tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

SMARCA4 p.Pro273= Likely benign ★ same residue
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

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-pro273ser (accessed [today's date]).

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