Is SOS2 p.Ser272= (c.816T>C) pathogenic?

SOS2 p.Ser272= (c.816T>C) is classified Benign in SOS2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.5%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with SOS2 p.Ser272= (c.816T>C)?

SOS2 p.Ser272= (c.816T>C) is associated with Cardiovascular phenotype, Noonan syndrome 9, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is SOS2 p.Ser272= (c.816T>C) in the general population?

SOS2 p.Ser272= (c.816T>C) is low-frequency (popmax 2.5%, nfe) (gnomAD).

SOS2 p.Ser272=

c.816T>C · rs35396088 · VCV475762

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.5%, nfe)

Conditions

Cardiovascular phenotype

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 1.1	GERP -2.1, phastCons 0.99
Overall
CADD	7.157	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.5% European (non-Finnish) · 29,525/1,179,590 alleles

Filtering AF 2.48% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.47%

Overall 2.33% 37,664/1,613,700 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	8.9%	11
European (non-Finnish)grpmax	2.5%	40
Remaining individualsnot grpmax-eligible	1.87%	54
Ashkenazi Jewishnot grpmax-eligible	1.36%	73
Admixed American	0.655%	153
African / African-American	0.368%	272
Middle Eastern	0.297%	337
South Asian	0.205%	487

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser272=
Coding: c.816T>C
MANE Select: NM_006939
dbSNP: rs35396088
Type: single nucleotide variant
Location: chr14:50182505 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.67 · 11 PDB
Residue 272: the dh domain

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 Noonan syndrome and Noonan-related syndrome

Similar variants

SOS2 p.Ser272Arg 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-ser272 (accessed [today's date]).

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