Is SOS2 p.Ser669Arg (c.2007T>A) pathogenic?

SOS2 p.Ser669Arg (c.2007T>A) is classified Conflicting classifications of pathogenicity in SOS2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.8962); Very rare (popmax 0.00533%, afr); Associated with Cardiovascular phenotype.

What condition is associated with SOS2 p.Ser669Arg (c.2007T>A)?

SOS2 p.Ser669Arg (c.2007T>A) is associated with Cardiovascular phenotype, Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Ser669Arg (c.2007T>A) in the general population?

SOS2 p.Ser669Arg (c.2007T>A) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about SOS2 p.Ser669Arg (c.2007T>A)?

AlphaMissense predicts likely pathogenic (score 0.8962) — an in-silico prediction, not a clinical call.

SOS2 p.Ser669Arg

c.2007T>A · VCV3624564

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8962 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8962	likely pathogenic
REVEL	0.235	benign-leaning
SaProt	LLR -5.79	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -3.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 29 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	19.21	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,024 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,612,782 alleles · very rare

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.Ser669Arg
Coding: c.2007T>A
MANE Select: NM_006939
Type: single nucleotide variant
Location: chr14:50157049 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 669: 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

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

Also linked: Noonan syndrome 9

Similar variants

SOS2 p.Ser669= Likely benign ★★ same residue
SOS2 p.Ser669Gly Likely benign ★ 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

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-ser669arg (accessed [today's date]).

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