Is SOS2 p.Pro994Ala (c.2980C>G) pathogenic?

SOS2 p.Pro994Ala (c.2980C>G) is classified Uncertain significance in SOS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-04). AlphaMissense: likely pathogenic (0.8006); Absent from gnomAD v4.1; Associated with Noonan syndrome 9.

What condition is associated with SOS2 p.Pro994Ala (c.2980C>G)?

SOS2 p.Pro994Ala (c.2980C>G) is associated with Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Pro994Ala (c.2980C>G) in the general population?

SOS2 p.Pro994Ala (c.2980C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SOS2 p.Pro994Ala (c.2980C>G)?

AlphaMissense predicts likely pathogenic (score 0.8006) — an in-silico prediction, not a clinical call.

SOS2 p.Pro994Ala

c.2980C>G · rs1883999639 · VCV1009985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8006 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Noonan syndrome 9

Computational evidence

Protein change
AlphaMissense	0.8006	likely pathogenic
REVEL	0.358	indeterminate
SaProt	LLR -12.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 29 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SOS2
Protein: p.Pro994Ala
Coding: c.2980C>G
MANE Select: NM_006939
dbSNP: rs1883999639
Type: single nucleotide variant
Location: chr14:50134218 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 994: the ras-gef domain; a turn

Full SOS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Noonan syndrome 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SOS2 p.Pro994Arg Uncertain significance ★ ⚠ same residue
SOS2 p.Pro994= Likely benign ★ same residue
SOS2 p.Pro994Thr 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

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-pro994ala (accessed [today's date]).

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