Is SOS1 p.Pro669= (c.2007C>G) pathogenic?

SOS1 p.Pro669= (c.2007C>G) is classified Likely benign in SOS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-07). Ultra-rare (popmax 0.0166%, mid); Associated with fibromatosis, gingival, 1.

What condition is associated with SOS1 p.Pro669= (c.2007C>G)?

SOS1 p.Pro669= (c.2007C>G) is associated with fibromatosis, gingival, 1, Noonan syndrome 4, RASopathy (ClinVar).

How common is SOS1 p.Pro669= (c.2007C>G) in the general population?

SOS1 p.Pro669= (c.2007C>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

SOS1 p.Pro669=

c.2007C>G · rs529749913 · VCV1583556

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

fibromatosis, gingival, 1

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 0.28	GERP 1.1, phastCons 0.95
Overall
CADD	4.185	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,040 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000623% 10/1,606,312 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,040
Admixed American	0.00334%	29,953
African / African-American	0.00267%	37,411
South Asian	0.0011%	90,948
European (non-Finnish)	0.000341%	293,356

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.Pro669=
Coding: c.2007C>G
MANE Select: NM_005633
dbSNP: rs529749913
Type: single nucleotide variant
Location: chr2:39013923 (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 669: an α-helix; the n-terminal ras-gef domain

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

Disease context

fibromatosis, gingival, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome 4 RASopathy

Similar variants

SOS1 p.Pro669Leu 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
SOS1 p.Glu846Lys 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-pro669 (accessed [today's date]).

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