Is SMARCA4 p.Pro223Ser (c.667C>T) pathogenic?

SMARCA4 p.Pro223Ser (c.667C>T) is classified Uncertain significance in SMARCA4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-12). AlphaMissense: likely benign (0.0644); Very rare (popmax 0.00244%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCA4 p.Pro223Ser (c.667C>T)?

SMARCA4 p.Pro223Ser (c.667C>T) is associated with hereditary neoplastic syndrome, rhabdoid tumor predisposition syndrome 2 (ClinVar).

How common is SMARCA4 p.Pro223Ser (c.667C>T) in the general population?

SMARCA4 p.Pro223Ser (c.667C>T) is very rare (popmax 0.00244%, eas) (gnomAD).

What do computational predictors say about SMARCA4 p.Pro223Ser (c.667C>T)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

SMARCA4 p.Pro223Ser

c.667C>T · rs2086046540 · VCV1754844

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.75	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 7.6	GERP 0.86, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 2,911 bp · p 0.24 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00244% East Asian · 1/40,954 alleles

Overall 0.000129% 2/1,547,090 alleles · very rare exomes 2/1,394,762 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00244%	40,954
European (non-Finnish)	8.72e-05%	1,147,357

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.Pro223Ser
Coding: c.667C>T
MANE Select: NM_003072
dbSNP: rs2086046540
Type: single nucleotide variant
Location: chr19:10986500 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 223: 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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: rhabdoid tumor predisposition syndrome 2

Similar variants

SMARCA4 p.Pro223Leu Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Pro223= 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-pro223ser (accessed [today's date]).

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