Is EPHB4 p.Arg889Trp (c.2665C>T) pathogenic?

EPHB4 p.Arg889Trp (c.2665C>T) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-11). AlphaMissense: likely benign (0.1898); Ultra-rare (popmax 0.019%, mid).

How common is EPHB4 p.Arg889Trp (c.2665C>T) in the general population?

EPHB4 p.Arg889Trp (c.2665C>T) is ultra-rare (popmax 0.019%, mid) (gnomAD).

What do computational predictors say about EPHB4 p.Arg889Trp (c.2665C>T)?

AlphaMissense predicts likely benign (score 0.1898) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg889Trp

c.2665C>T · rs762016655 · VCV1307567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1898	likely benign
REVEL	0.433	indeterminate
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -3.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% Middle Eastern · 1/5,260 alleles

Filtering AF 0.00159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00204% 31/1,521,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.019%	5,260
European (non-Finnish)	0.00229%	43,631
East Asian	0.00228%	43,886
Admixed American	0.00219%	45,626
African / African-American	0.00139%	71,872
South Asian	0.00131%	76,262

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: EPHB4
Protein: p.Arg889Trp
Coding: c.2665C>T
MANE Select: NM_004444
dbSNP: rs762016655
Type: single nucleotide variant
Location: chr7:100805514 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 889: a UniProt-annotated variant site (in cmavm2); the protein kinase domain; a UniProt-annotated variant site (in a gastric adenocarcinoma sample; somatic mutation)

Full EPHB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB4 p.Arg889Gln Likely benign ★ same residue
EPHB4 c.1691+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg394Ter Pathogenic ★★ same type
EPHB4 p.Arg431Ter Pathogenic ★★ same type
EPHB4 p.Arg739Gln Pathogenic ★★ 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/ephb4-p-arg889trp (accessed [today's date]).

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