Is SOS1 p.Ala596Pro (c.1786G>C) pathogenic?

SOS1 p.Ala596Pro (c.1786G>C) is classified Uncertain significance in SOS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely benign (0.2302); Very rare (popmax 0.00017%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with SOS1 p.Ala596Pro (c.1786G>C)?

SOS1 p.Ala596Pro (c.1786G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is SOS1 p.Ala596Pro (c.1786G>C) in the general population?

SOS1 p.Ala596Pro (c.1786G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about SOS1 p.Ala596Pro (c.1786G>C)?

AlphaMissense predicts likely benign (score 0.2302) — an in-silico prediction, not a clinical call.

SOS1 p.Ala596Pro

c.1786G>C · VCV3799909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2302	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -7.30	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 6.1	GERP 6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 538 bp · p 0.49 · regional, not allelic
Overall
CADD	23.3	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 0.00017% European (non-Finnish) · 2/1,179,390 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,350 alleles · very rare exomes 2/1,461,270 · genomes 0/152,080 · 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: SOS1
Protein: p.Ala596Pro
Coding: c.1786G>C
MANE Select: NM_005633
Type: single nucleotide variant
Location: chr2:39022642 (GRCh38)
Gene constraint: LOEUF 0.288 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.12 · 92 PDB
Residue 596: a turn

Full SOS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HGF p.Thr596Met Uncertain significance ★★ ⚠ same residue
HGF p.Thr596= Likely benign ★★ same residue
SOS1 p.Gly434Arg Pathogenic ★★ same condition
SOS1 p.Ile437Thr Pathogenic/Likely pathogenic ★★ same condition
SOS1 p.Leu550Pro Pathogenic/Likely pathogenic ★★ same condition
SOS1 c.720+1G>A Uncertain significance ★★ same condition
SOS1 p.Ala1162Val Uncertain significance ★★ ⚠ same condition
SOS1 p.Ala1164Glu 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/sos1-p-ala596pro (accessed [today's date]).

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