Is SMARCA2 p.Pro46Ser (c.136C>T) pathogenic?

SMARCA2 p.Pro46Ser (c.136C>T) is classified Uncertain significance in SMARCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-17). AlphaMissense: likely pathogenic (0.7472); Very rare (popmax 0.00331%, sas); Associated with intellectual disability.

What condition is associated with SMARCA2 p.Pro46Ser (c.136C>T)?

SMARCA2 p.Pro46Ser (c.136C>T) is associated with intellectual disability (ClinVar).

How common is SMARCA2 p.Pro46Ser (c.136C>T) in the general population?

SMARCA2 p.Pro46Ser (c.136C>T) is very rare (popmax 0.00331%, sas) (gnomAD).

What do computational predictors say about SMARCA2 p.Pro46Ser (c.136C>T)?

AlphaMissense predicts likely pathogenic (score 0.7472) — an in-silico prediction, not a clinical call.

SMARCA2 p.Pro46Ser

c.136C>T · VCV4075230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.7472	likely pathogenic
REVEL	0.53	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 11 kb · p 0.08 · regional, not allelic
Overall
CADD	25.6	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 0.00331% South Asian · 3/90,670 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.000186% 3/1,613,056 alleles · very rare exomes 3/1,460,708 · genomes 0/152,348 · 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.Pro46Ser
Coding: c.136C>T
MANE Select: NM_003070
Type: single nucleotide variant
Location: chr9:2029158 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.06 · 32 PDB
Residue 46: the 'disordered' region

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

Disease context

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

Similar variants

SMARCA2 p.Ala1201Val Pathogenic/Likely pathogenic ★★ same condition
SMARCA2 p.Arg505Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
SMARCA2 p.Arg525Cys Pathogenic ★★ same condition
SMARCA2 p.Arg525His Pathogenic/Likely pathogenic ★★ same condition
SMARCA2 p.Arg937His Pathogenic/Likely pathogenic ★★ same condition
SMARCA2 p.Ser783Trp Likely pathogenic ★★ same condition
SMARCA2 p.Arg937Cys Pathogenic ★ same condition
SMARCA2 p.Glu929Val 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/smarca2-p-pro46ser (accessed [today's date]).

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