Is SMARCA5 p.Pro339Ser (c.1015C>T) pathogenic?

SMARCA5 p.Pro339Ser (c.1015C>T) is classified Likely pathogenic in SMARCA5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-15). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with SMARCA5-associated neurodevelopmental disorder.

What condition is associated with SMARCA5 p.Pro339Ser (c.1015C>T)?

SMARCA5 p.Pro339Ser (c.1015C>T) is associated with SMARCA5-associated neurodevelopmental disorder (ClinVar).

How common is SMARCA5 p.Pro339Ser (c.1015C>T) in the general population?

SMARCA5 p.Pro339Ser (c.1015C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMARCA5 p.Pro339Ser (c.1015C>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

SMARCA5 p.Pro339Ser

c.1015C>T · VCV3773710

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SMARCA5-associated neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 5% in SMARCA5
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -15.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 84 bp · p 4.3e-08 · regional, not allelic
Overall
CADD	28.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMARCA5
Protein: p.Pro339Ser
Coding: c.1015C>T
MANE Select: NM_003601
Type: single nucleotide variant
Location: chr4:143528640 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.41 · 15 PDB
Residue 339: the helicase atp-binding domain

Full SMARCA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SMARCA5-associated neurodevelopmental disorder

Similar variants

SMARCA5 p.Pro339Ala Likely pathogenic ★ same residue
SMARCA5 p.Ala589Val Uncertain significance ★ ⚠ same condition
SMARCA5 p.Arg592Gln Uncertain significance ★ ⚠ same condition
SMARCA5 p.Arg764Leu Uncertain significance ★ ⚠ same condition
SMARCA5 p.Asn567Ser Uncertain significance ★ ⚠ same condition
SMARCA5 p.Lys834Glu Uncertain significance ★ ⚠ same condition
SMARCA5 p.Arg620His Uncertain significance ⚠ same condition
SMARCA5 p.Arg978Cys Uncertain significance ⚠ 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/smarca5-p-pro339ser (accessed [today's date]).

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