Is SH2B3 p.Ser134Pro (c.400T>C) pathogenic?

SH2B3 p.Ser134Pro (c.400T>C) is classified Uncertain significance in SH2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0764); Very rare (popmax 9.02e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SH2B3 p.Ser134Pro (c.400T>C)?

SH2B3 p.Ser134Pro (c.400T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SH2B3 p.Ser134Pro (c.400T>C) in the general population?

SH2B3 p.Ser134Pro (c.400T>C) is very rare (popmax 9.02e-05%, nfe) (gnomAD).

What do computational predictors say about SH2B3 p.Ser134Pro (c.400T>C)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

SH2B3 p.Ser134Pro

c.400T>C · VCV4630782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.02e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.62	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 -1.1	GERP -1.5
Regional constraint	o/e 1.14	unconstrained · MANE · 30 kb · p 4.6e-05 · regional, not allelic
Overall
CADD	13.24	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 9.02e-05% European (non-Finnish) · 1/1,108,400 alleles

Overall 6.87e-05% 1/1,456,444 alleles · very rare exomes 1/1,305,164 · genomes 0/151,280 · 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: SH2B3
Protein: p.Ser134Pro
Coding: c.400T>C
MANE Select: NM_005475
Type: single nucleotide variant
Location: chr12:111418545 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.45
Residue 134: the 'disordered' region

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.Ser134Cys Uncertain significance ★ ⚠ same residue
SH2B3 p.Ser134Phe Uncertain significance ★ ⚠ same residue
SH2B3 p.Ser134= 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

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-ser134pro (accessed [today's date]).

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