Is SOS2 p.Pro1063= (c.3189A>G) pathogenic?

SOS2 p.Pro1063= (c.3189A>G) is classified Likely benign in SOS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-11). Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with SOS2 p.Pro1063= (c.3189A>G)?

SOS2 p.Pro1063= (c.3189A>G) is associated with Cardiovascular phenotype, Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Pro1063= (c.3189A>G) in the general population?

SOS2 p.Pro1063= (c.3189A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

SOS2 p.Pro1063=

c.3189A>G · VCV3447380

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 -3.9	GERP -0.88
Overall
CADD	5.779	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,012 alleles

Overall 0.000124% 2/1,614,186 alleles · very rare exomes 1/1,461,846 · genomes 1/152,340 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Pro1063=
Coding: c.3189A>G
MANE Select: NM_006939
Type: single nucleotide variant
Location: chr14:50130649 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB

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.Pro1063Leu Uncertain significance ★ ⚠ same residue
SOS2 p.Pro1063fs Uncertain significance ★★ same residue
SOS2 p.Pro1063Thr Uncertain significance ★ ⚠ 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

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-pro1063 (accessed [today's date]).

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