Is SMARCA4 p.Pro153Leu (c.458C>T) pathogenic?

SMARCA4 p.Pro153Leu (c.458C>T) is classified Conflicting classifications of pathogenicity in SMARCA4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.081); Very rare (popmax 0.00446%, eas); Associated with rhabdoid tumor predisposition syndrome 2.

What condition is associated with SMARCA4 p.Pro153Leu (c.458C>T)?

SMARCA4 p.Pro153Leu (c.458C>T) is associated with rhabdoid tumor predisposition syndrome 2, intellectual disability, autosomal dominant 16, hereditary neoplastic syndrome (ClinVar).

How common is SMARCA4 p.Pro153Leu (c.458C>T) in the general population?

SMARCA4 p.Pro153Leu (c.458C>T) is very rare (popmax 0.00446%, eas) (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.Pro153Leu (c.458C>T)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

SMARCA4 p.Pro153Leu

c.458C>T · rs539710314 · VCV663612

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

rhabdoid tumor predisposition syndrome 2

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 2,200 bp · p 0.0027 · regional, not allelic
Overall
CADD	23.6	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 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00124% 20/1,613,774 alleles · very rare exomes 18/1,461,478 · genomes 2/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00133%	75,062
European (non-Finnish)	0.00127%	78,665
South Asian	0.0011%	91,082

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.Pro153Leu
Coding: c.458C>T
MANE Select: NM_003072
dbSNP: rs539710314
Type: single nucleotide variant
Location: chr19:10986291 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 153: 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: intellectual disability, autosomal dominant 16 hereditary neoplastic syndrome

For Rhabdoid tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

SMARCA4 p.Pro153Gln Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Pro153= 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

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-pro153leu (accessed [today's date]).

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