Is SH2B3 p.Phe138Ser (c.413T>C) pathogenic?

SH2B3 p.Phe138Ser (c.413T>C) is classified Uncertain significance in SH2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). AlphaMissense: ambiguous (0.4909); Very rare (popmax 0.00311%, eas); Associated with Inborn genetic diseases.

What condition is associated with SH2B3 p.Phe138Ser (c.413T>C)?

SH2B3 p.Phe138Ser (c.413T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SH2B3 p.Phe138Ser (c.413T>C) in the general population?

SH2B3 p.Phe138Ser (c.413T>C) is very rare (popmax 0.00311%, eas) (gnomAD).

What do computational predictors say about SH2B3 p.Phe138Ser (c.413T>C)?

AlphaMissense predicts ambiguous (score 0.4909) — an in-silico prediction, not a clinical call.

SH2B3 p.Phe138Ser

c.413T>C · VCV3795120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00311%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4909	ambiguous
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.75, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 30 kb · p 4.6e-05 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00311% East Asian · 1/32,174 alleles

Filtering AF 0.000193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000127%

Overall 0.000531% 7/1,319,158 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00311%	32,174
European (non-Finnish)	0.000537%	186,054

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.Phe138Ser
Coding: c.413T>C
MANE Select: NM_005475
Type: single nucleotide variant
Location: chr12:111418558 (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.Phe138= Likely benign ★ same residue
SH2B3 p.Phe138Leu Likely benign ★ 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-phe138ser (accessed [today's date]).

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