Is SOS1 p.Val180= (c.540A>G) pathogenic?

SOS1 p.Val180= (c.540A>G) is classified Likely benign in SOS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-10). Ultra-rare (popmax 0.0172%, mid); Associated with RASopathy.

What condition is associated with SOS1 p.Val180= (c.540A>G)?

SOS1 p.Val180= (c.540A>G) is associated with RASopathy (ClinVar).

How common is SOS1 p.Val180= (c.540A>G) in the general population?

SOS1 p.Val180= (c.540A>G) is ultra-rare (popmax 0.0172%, mid) (gnomAD).

SOS1 p.Val180=

c.540A>G · rs1671148614 · VCV1639912

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, mid)

Conditions

RASopathy

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 0.66	GERP -0.56, phastCons 1
Overall
CADD	7.257	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0172% Middle Eastern · 1/5,826 alleles

Filtering AF 0.000372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000139%

Overall 0.000362% 5/1,382,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0172%	5,826
Remaining individualsnot grpmax-eligible	0.00334%	29,945
South Asian	0.00224%	44,630

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: SOS1
Protein: p.Val180=
Coding: c.540A>G
MANE Select: NM_005633
dbSNP: rs1671148614
Type: single nucleotide variant
Location: chr2:39054794 (GRCh38)
Gene constraint: LOEUF 0.288 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.12 · 92 PDB
Residue 180: an α-helix

Full SOS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SOS1 p.Val180Ile Uncertain significance ★ ⚠ same residue
SOS1 p.Val180Ala Uncertain significance ★ ⚠ same residue
SOS1 p.Arg552Gly Pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Lys Pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Met Likely pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Ser Pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Thr Pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Trp 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/sos1-p-val180 (accessed [today's date]).

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