Is SH2B3 p.Pro243Ser (c.727C>T) pathogenic?

SH2B3 p.Pro243Ser (c.727C>T) is classified Uncertain significance in SH2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.8075); Very rare (popmax 9.14e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SH2B3 p.Pro243Ser (c.727C>T)?

SH2B3 p.Pro243Ser (c.727C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SH2B3 p.Pro243Ser (c.727C>T) in the general population?

SH2B3 p.Pro243Ser (c.727C>T) is very rare (popmax 9.14e-05%, nfe) (gnomAD).

What do computational predictors say about SH2B3 p.Pro243Ser (c.727C>T)?

AlphaMissense predicts likely pathogenic (score 0.8075) — an in-silico prediction, not a clinical call.

SH2B3 p.Pro243Ser

c.727C>T · VCV3953514

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.14e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8075	likely pathogenic
REVEL	0.306	indeterminate
SaProt	LLR -11.43	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.97, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 30 kb · p 4.6e-05 · regional, not allelic
Overall
CADD	26.4	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

Grpmax group 9.14e-05% European (non-Finnish) · 1/1,094,188 alleles

Overall 7.97e-05% 1/1,255,114 alleles · very rare

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.Pro243Ser
Coding: c.727C>T
MANE Select: NM_005475
Type: single nucleotide variant
Location: chr12:111418872 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.45
Residue 243: the ph domain; a UniProt-annotated variant site (found in a patient with isolated erythrocytosis; uncertain significance)

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.Pro243= Benign/Likely benign ★★ same residue
SH2B3 p.Pro243Arg 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

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-pro243ser (accessed [today's date]).

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