Is SMARCA4 p.Pro55Ser (c.163C>T) pathogenic?

SMARCA4 p.Pro55Ser (c.163C>T) is classified Conflicting classifications of pathogenicity in SMARCA4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-20). AlphaMissense: likely benign (0.0479); Very rare (popmax 0.00401%, afr); Associated with intellectual disability, autosomal dominant 16.

What condition is associated with SMARCA4 p.Pro55Ser (c.163C>T)?

SMARCA4 p.Pro55Ser (c.163C>T) is associated with intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, hereditary neoplastic syndrome (ClinVar).

How common is SMARCA4 p.Pro55Ser (c.163C>T) in the general population?

SMARCA4 p.Pro55Ser (c.163C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about SMARCA4 p.Pro55Ser (c.163C>T)?

AlphaMissense predicts likely benign (score 0.0479) — an in-silico prediction, not a clinical call.

SMARCA4 p.Pro55Ser

c.163C>T · rs1218848193 · VCV484891

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 16

Computational evidence

Protein change
AlphaMissense	0.0479	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -6.60	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 0.58	GERP 0.11, phastCons 0.8
Regional constraint	o/e 0.81	unconstrained · MANE · 2,200 bp · p 0.0027 · regional, not allelic
Overall
CADD	23.0	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 0.00401% African / African-American · 3/74,764 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000249% 4/1,605,246 alleles · very rare exomes 2/1,453,026 · genomes 2/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,921
European (non-Finnish)	8.5e-05%	1,176,345

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.Pro55Ser
Coding: c.163C>T
MANE Select: NM_003072
dbSNP: rs1218848193
Type: single nucleotide variant
Location: chr19:10984314 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 55: 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

intellectual disability, autosomal dominant 16 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: rhabdoid tumor predisposition syndrome 2 hereditary neoplastic syndrome

Similar variants

SMARCA4 p.Pro55Leu Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Pro55Ala Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro55= 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

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-pro55ser (accessed [today's date]).

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