Is SOS2 p.Pro191Arg (c.572C>G) pathogenic?

SOS2 p.Pro191Arg (c.572C>G) is classified Benign/Likely benign in SOS2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.19); Rare (popmax 0.941%, nfe); Associated with Noonan syndrome 9.

What condition is associated with SOS2 p.Pro191Arg (c.572C>G)?

SOS2 p.Pro191Arg (c.572C>G) is associated with Noonan syndrome 9, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is SOS2 p.Pro191Arg (c.572C>G) in the general population?

SOS2 p.Pro191Arg (c.572C>G) is rare (popmax 0.941%, nfe) (gnomAD).

What do computational predictors say about SOS2 p.Pro191Arg (c.572C>G)?

AlphaMissense predicts likely benign (score 0.19) — an in-silico prediction, not a clinical call.

SOS2 p.Pro191Arg

c.572C>G · rs72681869 · VCV445489

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.19 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.941%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Noonan syndrome 9

Computational evidence

Protein change
AlphaMissense	0.19	likely benign
REVEL	0.52	indeterminate
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 72 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.941% European (non-Finnish) · 11,070/1,176,854 alleles

Filtering AF 0.926% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.92%

Overall 0.744% 11,977/1,609,034 alleles · rare exomes 11,340/1,456,788 · genomes 637/152,246 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.941%	106
Remaining individualsnot grpmax-eligible	0.815%	123
Amishnot grpmax-eligible	0.439%	228
Admixed American	0.263%	380
Finnishnot grpmax-eligible	0.142%	702
African / African-American	0.112%	891
Ashkenazi Jewishnot grpmax-eligible	0.088%	1,137
Middle Eastern	0.0662%	1,512
South Asian	0.0364%	2,744
East Asian	0.00223%	44,816

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.Pro191Arg
Coding: c.572C>G
MANE Select: NM_006939
dbSNP: rs72681869
Type: single nucleotide variant
Location: chr14:50188639 (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

Also linked: Noonan syndrome and Noonan-related syndrome

Similar variants

SOS2 p.Pro191His Uncertain significance ★ ⚠ same residue
SOS2 p.Pro191Leu 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

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-pro191arg (accessed [today's date]).

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