Is SH2B3 p.Phe431Ser (c.1292T>C) pathogenic?

SH2B3 p.Phe431Ser (c.1292T>C) is classified Uncertain significance in SH2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-01). AlphaMissense: likely pathogenic (0.9981); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SH2B3 p.Phe431Ser (c.1292T>C)?

SH2B3 p.Phe431Ser (c.1292T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SH2B3 p.Phe431Ser (c.1292T>C) in the general population?

SH2B3 p.Phe431Ser (c.1292T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SH2B3 p.Phe431Ser (c.1292T>C)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

SH2B3 p.Phe431Ser

c.1292T>C · VCV4842820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic · top 1% in SH2B3
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -15.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 30 kb · p 4.6e-05 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SH2B3
Protein: p.Phe431Ser
Coding: c.1292T>C
MANE Select: NM_005475
Type: single nucleotide variant
Location: chr12:111447711 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.45
Residue 431: a UniProt-annotated variant site (found in a patient with isolated erythrocytosis; uncertain significance); the sh2 domain

Full SH2B3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SH2B3 p.Phe431Leu Uncertain significance ★ ⚠ same residue
SH2B3 p.Phe431= Likely benign ★ same residue
SH2B3 p.Ala161Val Uncertain significance ★★ ⚠ same condition
SH2B3 p.Ala174Thr Uncertain significance ★★ ⚠ same condition
SH2B3 p.Ala300Thr Uncertain significance ★★ ⚠ same condition
SH2B3 p.Arg221Met Uncertain significance ★★ ⚠ same condition
SH2B3 p.Arg226Trp Uncertain significance ★★ ⚠ same condition
SH2B3 p.Arg235Cys Uncertain significance ★★ ⚠ 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/sh2b3-p-phe431ser (accessed [today's date]).

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