Is SOS2 p.Pro1058= (c.3174A>G) pathogenic?

SOS2 p.Pro1058= (c.3174A>G) is classified Likely benign in SOS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). Very rare (popmax 0.000424%, nfe); Associated with Noonan syndrome 9.

What condition is associated with SOS2 p.Pro1058= (c.3174A>G)?

SOS2 p.Pro1058= (c.3174A>G) is associated with Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Pro1058= (c.3174A>G) in the general population?

SOS2 p.Pro1058= (c.3174A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

SOS2 p.Pro1058=

c.3174A>G · rs763708050 · VCV1642326

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

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 -0.64	GERP -3.5, phastCons 0.019
Overall
CADD	6.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,998 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,148 alleles · very rare exomes 5/1,461,828 · genomes 0/152,320 · 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: SOS2
Protein: p.Pro1058=
Coding: c.3174A>G
MANE Select: NM_006939
dbSNP: rs763708050
Type: single nucleotide variant
Location: chr14:50130664 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 1058: 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.Pro1058Arg Uncertain significance ★★ ⚠ same residue
SOS2 p.Pro1058Leu Uncertain significance ★ ⚠ same residue
SOS2 p.Pro1058Ser 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-pro1058 (accessed [today's date]).

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