Is EPHB2 p.Arg745Cys (c.2233C>T) pathogenic?

EPHB2 p.Arg745Cys (c.2233C>T) is classified Pathogenic in EPHB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.995); Very rare (popmax 0.00667%, amr); Associated with bleeding disorder, platelet-type, 22.

What condition is associated with EPHB2 p.Arg745Cys (c.2233C>T)?

EPHB2 p.Arg745Cys (c.2233C>T) is associated with bleeding disorder, platelet-type, 22 (ClinVar).

How common is EPHB2 p.Arg745Cys (c.2233C>T) in the general population?

EPHB2 p.Arg745Cys (c.2233C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about EPHB2 p.Arg745Cys (c.2233C>T)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

EPHB2 p.Arg745Cys

c.2233C>T · rs761749948 · VCV633783

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

bleeding disorder, platelet-type, 22

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic ✓ concordant with ClinVar
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -15.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 203 kb · p 2.4e-23 · regional, not allelic
Overall
CADD	34.0	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 0.00667% Admixed American · 4/60,014 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000434% 7/1,614,142 alleles · very rare exomes 5/1,461,894 · genomes 2/152,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,004
South Asian	0.0011%	91,088
European (non-Finnish)	0.000169%	590,030

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: EPHB2
Protein: p.Arg745Cys
Coding: c.2233C>T
MANE Select: NM_017449
dbSNP: rs761749948
Type: single nucleotide variant
Location: chr1:22908049 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 5 PDB
Residue 745: the protein kinase domain; a UniProt-annotated variant site (in bdplt22)

Full EPHB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

bleeding disorder, platelet-type, 22 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB2 p.Pro795Gln Uncertain significance ★ ⚠ same condition
EPHB2 c.*174_*181dup Uncertain significance ★ same condition
EPHB2 c.*214_*215del Uncertain significance ★ same condition
EPHB2 p.Val414Ile Uncertain significance ★★ ⚠ same type
EPHB2 c.1766-9G>T Benign/Likely benign ★★ same type
EPHB2 p.Ala279Ser Benign ★★ same type
EPHB2 p.Asn242= Likely benign ★★ same type
EPHB2 p.Asp574= Benign ★★ same type

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/ephb2-p-arg745cys (accessed [today's date]).

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