Is SOS2 p.Val683= (c.2049A>G) pathogenic?

SOS2 p.Val683= (c.2049A>G) is classified Likely benign in SOS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Very rare (popmax 0.00429%, nfe); Associated with Noonan syndrome 9.

What condition is associated with SOS2 p.Val683= (c.2049A>G)?

SOS2 p.Val683= (c.2049A>G) is associated with Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Val683= (c.2049A>G) in the general population?

SOS2 p.Val683= (c.2049A>G) is very rare (popmax 0.00429%, nfe) (gnomAD).

SOS2 p.Val683=

c.2049A>G · rs748361433 · VCV1545284

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00429%, 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 0.051	GERP -3.8, phastCons 0.93
Overall
CADD	7.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00429% European (non-Finnish) · 50/1,164,556 alleles

Filtering AF 0.0033% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00298%

Overall 0.00362% 52/1,436,926 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00429%	23,291
Remaining individualsnot grpmax-eligible	0.00326%	30,675

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.Val683=
Coding: c.2049A>G
MANE Select: NM_006939
dbSNP: rs748361433
Type: single nucleotide variant
Location: chr14:50157007 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 683: the n-terminal ras-gef domain; an α-helix

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.Val683Ile 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
SOS2 p.Asn867Ser Likely benign ★★★ same condition
SOS2 p.Met267Arg Pathogenic/Likely pathogenic ★★ ⚠ 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-val683 (accessed [today's date]).

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