Is SOS2 p.Ser1111Phe (c.3332C>T) pathogenic?

SOS2 p.Ser1111Phe (c.3332C>T) is classified Uncertain significance in SOS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-05). AlphaMissense: likely benign (0.129); Very rare (popmax 0.00017%, nfe); Associated with Noonan syndrome 9.

What condition is associated with SOS2 p.Ser1111Phe (c.3332C>T)?

SOS2 p.Ser1111Phe (c.3332C>T) is associated with Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Ser1111Phe (c.3332C>T) in the general population?

SOS2 p.Ser1111Phe (c.3332C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about SOS2 p.Ser1111Phe (c.3332C>T)?

AlphaMissense predicts likely benign (score 0.129) — an in-silico prediction, not a clinical call.

SOS2 p.Ser1111Phe

c.3332C>T · rs2502824417 · VCV2162547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.129 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Noonan syndrome 9

Computational evidence

Protein change
AlphaMissense	0.129	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 12 kb · p 0.74 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,530 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,154 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.Ser1111Phe
Coding: c.3332C>T
MANE Select: NM_006939
dbSNP: rs2502824417
Type: single nucleotide variant
Location: chr14:50130506 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB

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.Ser1111Cys 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-ser1111phe (accessed [today's date]).

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