Is SOS1 p.Arg65= (c.195A>C) pathogenic?

SOS1 p.Arg65= (c.195A>C) is classified Benign in SOS1 (ClinVar, Expert panel, 17 submitters; last evaluated 2017-04-18). Common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with RASopathy.

What condition is associated with SOS1 p.Arg65= (c.195A>C)?

SOS1 p.Arg65= (c.195A>C) is associated with RASopathy, fibromatosis, gingival, 1, Noonan syndrome 4 (ClinVar).

SOS1 p.Arg65=

Q: How common is SOS1 p.Arg65= (c.195A>C) in the general population?

SOS1 p.Arg65= (c.195A>C) is common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.195A>C · rs7609455 · VCV40643

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 17 submitters

gnomAD v4.1

Common

common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.195A>C (p.Arg65=) variant in the SOS1 gene is 10.978% (1192/10346) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 2.8	GERP -0.64, phastCons 1
Overall
CADD	9.282	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.8% African / African-American · 8,823/74,900 alleles

Filtering AF 11.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.5%

Overall 0.822% 13,266/1,613,400 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.8%	8
East Asian	3.22%	31
Admixed American	1.59%	63
Remaining individualsnot grpmax-eligible	1.17%	86
Middle Eastern	0.825%	121
South Asian	0.736%	136
Finnishnot grpmax-eligible	0.112%	889
European (non-Finnish)	0.0445%	2,247
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,865

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.Arg65=
Coding: c.195A>C
MANE Select: NM_005633
dbSNP: rs7609455
Type: single nucleotide variant
Location: chr2:39067646 (GRCh38)
Gene constraint: LOEUF 0.288 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.12 · 92 PDB

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

Also linked: fibromatosis, gingival, 1 Noonan syndrome 4 Noonan syndrome and Noonan-related syndrome

Similar variants

SOS1 p.Arg65Gln Uncertain significance ★ same residue
SOS1 p.Arg65Ter 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-arg65 (accessed [today's date]).

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