Is SH2B3 p.Pro53= (c.159G>C) pathogenic?

SH2B3 p.Pro53= (c.159G>C) is classified Likely benign in SH2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). Very rare (popmax 0.00119%, sas); Associated with Inborn genetic diseases.

What condition is associated with SH2B3 p.Pro53= (c.159G>C)?

SH2B3 p.Pro53= (c.159G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SH2B3 p.Pro53= (c.159G>C) in the general population?

SH2B3 p.Pro53= (c.159G>C) is very rare (popmax 0.00119%, sas) (gnomAD).

SH2B3 p.Pro53=

c.159G>C · VCV3440789

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.47	GERP -2.4, phastCons 0.007
Overall
CADD	4.609	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% South Asian · 1/84,128 alleles

Overall 0.000131% 2/1,531,800 alleles · very rare exomes 2/1,379,654 · genomes 0/152,146 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00119%	84,128
European (non-Finnish)	8.73e-05%	1,145,314

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.Pro53=
Coding: c.159G>C
MANE Select: NM_005475
Type: single nucleotide variant
Location: chr12:111418304 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.45

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.Pro53Ala Uncertain significance ★ ⚠ same residue
SH2B3 p.Pro53Arg Uncertain significance ★ ⚠ same residue
SH2B3 p.Pro53Gln 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

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-pro53 (accessed [today's date]).

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