Is SOS2 p.Pro1318= (c.3954A>G) pathogenic?

SOS2 p.Pro1318= (c.3954A>G) is classified Likely benign in SOS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-18). Very rare (popmax 0.00401%, afr); Associated with Noonan syndrome 9.

What condition is associated with SOS2 p.Pro1318= (c.3954A>G)?

SOS2 p.Pro1318= (c.3954A>G) is associated with Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Pro1318= (c.3954A>G) in the general population?

SOS2 p.Pro1318= (c.3954A>G) is very rare (popmax 0.00401%, afr) (gnomAD).

SOS2 p.Pro1318=

c.3954A>G · rs751408063 · VCV1107037

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Noonan syndrome 9

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 -2.4	GERP -1.1
Overall
CADD	2.444	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,892 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00155% 25/1,613,926 alleles · very rare exomes 23/1,461,852 · genomes 2/152,074 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,964
East Asian	0.00223%	44,894
European (non-Finnish)	0.00178%	56,190

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.Pro1318=
Coding: c.3954A>G
MANE Select: NM_006939
dbSNP: rs751408063
Type: single nucleotide variant
Location: chr14:50118389 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 1318: the 'disordered' region

Full SOS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Noonan syndrome 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SOS2 p.Pro1318Gln Uncertain significance ★★ ⚠ same residue
SOS2 p.Pro1318Ser Benign/Likely benign ★★ same residue
SOS2 p.Pro1318Thr Uncertain significance ★ ⚠ same residue
SOS2 p.Pro1318Ala Benign ★ same residue
SOS2 p.Pro1318Leu 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

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-pro1318 (accessed [today's date]).

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