Is SOS2 p.Ile596Phe (c.1786A>T) pathogenic?

SOS2 p.Ile596Phe (c.1786A>T) is classified Uncertain significance in SOS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: likely pathogenic (0.576); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with SOS2 p.Ile596Phe (c.1786A>T)?

SOS2 p.Ile596Phe (c.1786A>T) is associated with Cardiovascular phenotype (ClinVar).

How common is SOS2 p.Ile596Phe (c.1786A>T) in the general population?

SOS2 p.Ile596Phe (c.1786A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SOS2 p.Ile596Phe (c.1786A>T)?

AlphaMissense predicts likely pathogenic (score 0.576) — an in-silico prediction, not a clinical call.

SOS2 p.Ile596Phe

c.1786A>T · rs2502987934 · VCV3225957

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.576 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.576	likely pathogenic
REVEL	0.248	benign-leaning
SaProt	LLR -10.52	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 72 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	23.6	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

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: SOS2
Protein: p.Ile596Phe
Coding: c.1786A>T
MANE Select: NM_006939
dbSNP: rs2502987934
Type: single nucleotide variant
Location: chr14:50159497 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 596: the n-terminal ras-gef domain; a β-strand

Full SOS2 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

SOS2 p.Ile596Met Uncertain significance ★ ⚠ same residue
SOS2 p.Ile596Val Uncertain significance ★ ⚠ same residue
SOS2 c.346-3C>T Uncertain significance ★★ same condition
SOS2 p.Ala1119Val Uncertain significance ★★ ⚠ same condition
SOS2 p.Ala62Val Uncertain significance ★★ ⚠ same condition
SOS2 p.Ala743Gly Uncertain significance ★★ ⚠ same condition
SOS2 p.Ala890Thr Uncertain significance ★★ ⚠ same condition
SOS2 p.Arg1222Leu 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/sos2-p-ile596phe (accessed [today's date]).

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