Is SOS1 p.Leu1326Val (c.3976C>G) pathogenic?

SOS1 p.Leu1326Val (c.3976C>G) is classified Uncertain significance in SOS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: likely benign (0.0948); Very rare (popmax 0.00401%, afr); Associated with RASopathy.

What condition is associated with SOS1 p.Leu1326Val (c.3976C>G)?

SOS1 p.Leu1326Val (c.3976C>G) is associated with RASopathy (ClinVar).

How common is SOS1 p.Leu1326Val (c.3976C>G) in the general population?

SOS1 p.Leu1326Val (c.3976C>G) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about SOS1 p.Leu1326Val (c.3976C>G)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

SOS1 p.Leu1326Val

c.3976C>G · VCV4752126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 3.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,424 bp · p 0.35 · regional, not allelic
Overall
CADD	23.8	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 0.00401% African / African-American · 3/74,886 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,732 alleles · very rare exomes 1/1,461,548 · genomes 2/152,184 · joint denominator

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.Leu1326Val
Coding: c.3976C>G
MANE Select: NM_005633
Type: single nucleotide variant
Location: chr2:38985850 (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 1326: 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.Leu1326Pro Uncertain significance ★★ ⚠ same residue
SOS1 p.Leu1326Arg Likely benign ★ 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
SOS1 p.Arg552Trp 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/sos1-p-leu1326val (accessed [today's date]).

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