Is SH2B3 p.Pro243= (c.729C>T) pathogenic?

SH2B3 p.Pro243= (c.729C>T) is classified Benign/Likely benign in SH2B3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-12). Rare (popmax 0.684%, afr); Associated with Inborn genetic diseases.

What condition is associated with SH2B3 p.Pro243= (c.729C>T)?

SH2B3 p.Pro243= (c.729C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SH2B3 p.Pro243= (c.729C>T) in the general population?

SH2B3 p.Pro243= (c.729C>T) is rare (popmax 0.684%, afr) (gnomAD).

SH2B3 p.Pro243=

c.729C>T · rs539284730 · VCV733919

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.684%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.97, phastCons 1
Overall
CADD	13.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.684% African / African-American · 448/65,540 alleles

Filtering AF 0.631% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.611%

Overall 0.0342% 481/1,406,358 alleles · rare exomes 168/1,254,004 · genomes 313/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.684%	146
Admixed American	0.0462%	2,163
Remaining individualsnot grpmax-eligible	0.0353%	2,837
Middle Eastern	0.0259%	3,866

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.Pro243=
Coding: c.729C>T
MANE Select: NM_005475
dbSNP: rs539284730
Type: single nucleotide variant
Location: chr12:111418874 (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.Pro243Arg Uncertain significance ★ ⚠ same residue
SH2B3 p.Pro243Ser 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-pro243 (accessed [today's date]).

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