Is SH2B3 p.Ser486= (c.1458A>G) pathogenic?

SH2B3 p.Ser486= (c.1458A>G) is classified Likely benign in SH2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with SH2B3 p.Ser486= (c.1458A>G)?

SH2B3 p.Ser486= (c.1458A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SH2B3 p.Ser486= (c.1458A>G) in the general population?

SH2B3 p.Ser486= (c.1458A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

SH2B3 p.Ser486=

c.1458A>G · VCV3953407

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 0.068	GERP -1.3, phastCons 0.83
Overall
CADD	6.447	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,852 alleles

Overall 6.21e-05% 1/1,611,002 alleles · very rare exomes 1/1,458,966 · genomes 0/152,036 · 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.Ser486=
Coding: c.1458A>G
MANE Select: NM_005475
Type: single nucleotide variant
Location: chr12:111448032 (GRCh38)
Gene constraint: LOEUF 1.35 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.45
Residue 486: 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.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
SH2B3 p.Asp231Tyr 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-ser486 (accessed [today's date]).

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