Is SH2B3 p.Ser9Pro (c.25T>C) pathogenic?

SH2B3 p.Ser9Pro (c.25T>C) is classified Uncertain significance in SH2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely benign (0.0721); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SH2B3 p.Ser9Pro (c.25T>C)?

SH2B3 p.Ser9Pro (c.25T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SH2B3 p.Ser9Pro (c.25T>C) in the general population?

SH2B3 p.Ser9Pro (c.25T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SH2B3 p.Ser9Pro (c.25T>C)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

SH2B3 p.Ser9Pro

c.25T>C · VCV3953391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,549,764)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -5.24	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 -0.27	GERP -2.2, phastCons 0.001
Regional constraint	o/e 1.14	unconstrained · MANE · 30 kb · p 4.6e-05 · regional, not allelic
Overall
CADD	6.658	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

No allele count reported in gnomAD v4.1 (AN 1,549,764). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SH2B3
Protein: p.Ser9Pro
Coding: c.25T>C
MANE Select: NM_005475
Type: single nucleotide variant
Location: chr12:111418170 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.45
Residue 9: 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.Ser9Ala Uncertain significance ★ ⚠ 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
SH2B3 p.Arg39Gln 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-ser9pro (accessed [today's date]).

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