Is SOS2 p.Ser747= (c.2241C>T) pathogenic?

SOS2 p.Ser747= (c.2241C>T) is classified Uncertain significance in SOS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-09-03). Very rare (popmax 0.00119%, nfe); Associated with Noonan syndrome 9.

What condition is associated with SOS2 p.Ser747= (c.2241C>T)?

SOS2 p.Ser747= (c.2241C>T) is associated with Noonan syndrome 9 (ClinVar).

How common is SOS2 p.Ser747= (c.2241C>T) in the general population?

SOS2 p.Ser747= (c.2241C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

SOS2 p.Ser747=

c.2241C>T · rs1230203021 · VCV2195748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Conditions

Noonan syndrome 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.57	donor gain · deltas
Pangolin	Δ0.46	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.1, phastCons 1
Overall
CADD	18.39	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,179,150 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000958% 14/1,460,916 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.Ser747=
Coding: c.2241C>T
MANE Select: NM_006939
dbSNP: rs1230203021
Type: single nucleotide variant
Location: chr14:50150151 (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.Ser747Asn 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-ser747 (accessed [today's date]).

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