Is SOS2 p.Lys663= (c.1989A>G) pathogenic?

SOS2 p.Lys663= (c.1989A>G) is classified Conflicting classifications of pathogenicity in SOS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-22). Very rare (popmax 0.00267%, afr); Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with SOS2 p.Lys663= (c.1989A>G)?

SOS2 p.Lys663= (c.1989A>G) is associated with Noonan syndrome and Noonan-related syndrome, Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Lys663= (c.1989A>G) in the general population?

SOS2 p.Lys663= (c.1989A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

SOS2 p.Lys663=

c.1989A>G · rs1488158197 · VCV1112815

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Noonan syndrome and Noonan-related syndrome

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 2.9	GERP -3.8, phastCons 1
Overall
CADD	11.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,908 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,612,646 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,454
European (non-Finnish)	8.48e-05%	1,179,149

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.Lys663=
Coding: c.1989A>G
MANE Select: NM_006939
dbSNP: rs1488158197
Type: single nucleotide variant
Location: chr14:50157067 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 663: 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 and Noonan-related syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome 9

Similar variants

SOS2 p.Lys663Arg 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-lys663 (accessed [today's date]).

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