Is SMARCA2 p.Pro199Ser (c.595C>T) pathogenic?

SMARCA2 p.Pro199Ser (c.595C>T) is classified Uncertain significance in SMARCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). AlphaMissense: likely benign (0.1918); Very rare (popmax 6.2e-05%).

How common is SMARCA2 p.Pro199Ser (c.595C>T) in the general population?

SMARCA2 p.Pro199Ser (c.595C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about SMARCA2 p.Pro199Ser (c.595C>T)?

AlphaMissense predicts likely benign (score 0.1918) — an in-silico prediction, not a clinical call.

SMARCA2 p.Pro199Ser

c.595C>T · VCV4902333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1918	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -8.32	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 138 bp · p 5e-05 · regional, not allelic
Overall
CADD	25.2	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 6.2e-05%

Overall 6.2e-05% 1/1,614,002 alleles · very rare exomes 1/1,461,662 · genomes 0/152,340 · 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: SMARCA2
Protein: p.Pro199Ser
Coding: c.595C>T
MANE Select: NM_003070
Type: single nucleotide variant
Location: chr9:2039705 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.06 · 32 PDB
Residue 199: the qlq domain

Full SMARCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMARCA2 p.Pro199= Benign/Likely benign ★★ same residue
SMARCA2 p.Ala1138Pro Pathogenic/Likely pathogenic ★★ same type
SMARCA2 p.Ala1160Gly Pathogenic ★★ same type
SMARCA2 p.Ala1201Glu Pathogenic/Likely pathogenic ★★ same type
SMARCA2 p.Ala1201Val Pathogenic/Likely pathogenic ★★ same type
SMARCA2 p.Arg1105Cys Pathogenic ★★ same type
SMARCA2 p.Arg1105His Pathogenic ★★ same type
SMARCA2 p.Arg1105Pro Pathogenic/Likely pathogenic ★★ same type

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/smarca2-p-pro199ser (accessed [today's date]).

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