Is SOS2 p.Pro1093= (c.3279A>C) pathogenic?

SOS2 p.Pro1093= (c.3279A>C) is classified Likely benign in SOS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-09). Ultra-rare (popmax 0.0164%, mid); Associated with Cardiovascular phenotype.

What condition is associated with SOS2 p.Pro1093= (c.3279A>C)?

SOS2 p.Pro1093= (c.3279A>C) is associated with Cardiovascular phenotype, Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Pro1093= (c.3279A>C) in the general population?

SOS2 p.Pro1093= (c.3279A>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

SOS2 p.Pro1093=

c.3279A>C · rs780697283 · VCV719880

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -3.4
Overall
CADD	4.066	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00105% 17/1,613,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00934%	10,703
European (non-Finnish)	0.000763%	131,090

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: SOS2
Protein: p.Pro1093=
Coding: c.3279A>C
MANE Select: NM_006939
dbSNP: rs780697283
Type: single nucleotide variant
Location: chr14:50130559 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 1093: the 'disordered' region

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

Also linked: Noonan syndrome 9

Similar variants

SOS2 p.Pro1093Ser Uncertain significance ★★ ⚠ same residue
SOS2 p.Pro1093Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
SOS2 p.Met267Lys Likely pathogenic ★★★ ⚠ same condition
SOS2 p.Ala1195Val Uncertain significance ★★★ ⚠ same condition
SOS2 p.Arg225Gln Uncertain significance ★★★ ⚠ same condition
SOS2 p.Arg986Lys Uncertain significance ★★★ ⚠ same condition
SOS2 p.Thr1079Ala Uncertain significance ★★★ ⚠ same condition
SOS2 p.Asn867Ser Likely benign ★★★ 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-pro1093 (accessed [today's date]).

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