Is SOS1 p.Pro1237Thr (c.3709C>A) pathogenic?

SOS1 p.Pro1237Thr (c.3709C>A) is classified Likely benign in SOS1 (ClinVar, Expert panel, 7 submitters; last evaluated 2017-04-18). AlphaMissense: likely benign (0.1333); Ultra-rare (popmax 0.0692%, sas); Associated with RASopathy.

What condition is associated with SOS1 p.Pro1237Thr (c.3709C>A)?

SOS1 p.Pro1237Thr (c.3709C>A) is associated with RASopathy (ClinVar).

How common is SOS1 p.Pro1237Thr (c.3709C>A) in the general population?

SOS1 p.Pro1237Thr (c.3709C>A) is ultra-rare (popmax 0.0692%, sas) (gnomAD).

What do computational predictors say about SOS1 p.Pro1237Thr (c.3709C>A)?

AlphaMissense predicts likely benign (score 0.1333) — an in-silico prediction, not a clinical call.

SOS1 p.Pro1237Thr

c.3709C>A · rs371408734 · VCV45367

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1333 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0692%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Likely Benign for RASopathy. Applied ACMG criteria (verbatim):

BS1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.3709C>A (p.Pro1237Thr) variant in the SOS1 gene is 0.0373% (11/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1333	likely benign
REVEL	0.428	indeterminate
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 3.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,424 bp · p 0.35 · regional, not allelic
Overall
CADD	26.2	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 0.0692% South Asian · 63/91,074 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0505%

Overall 0.0049% 79/1,613,718 alleles · ultra-rare exomes 77/1,461,682 · genomes 2/152,036 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0692%	1,446
African / African-American	0.00401%	24,950
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
Admixed American	0.00167%	59,962
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	0.000848%	117,990

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: SOS1
Protein: p.Pro1237Thr
Coding: c.3709C>A
MANE Select: NM_005633
dbSNP: rs371408734
Type: single nucleotide variant
Location: chr2:38986117 (GRCh38)
Gene constraint: LOEUF 0.288 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.12 · 92 PDB
Residue 1237: the 'disordered' region

Full SOS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SOS1 p.Pro1237Ser Uncertain significance ★★ ⚠ same residue
SOS1 p.Pro1237Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
SOS1 p.Pro1237Leu Uncertain significance ★ ⚠ same residue
SOS1 p.Arg552Gly Pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Lys Pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Met Likely pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Ser Pathogenic ★★★ ⚠ same condition
SOS1 p.Arg552Thr 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/sos1-p-pro1237thr (accessed [today's date]).

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