Is EPHB4 p.Arg535Trp (c.1603C>T) pathogenic?

EPHB4 p.Arg535Trp (c.1603C>T) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-14). AlphaMissense: likely benign (0.2621); Rare (popmax 0.148%, mid); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg535Trp (c.1603C>T)?

EPHB4 p.Arg535Trp (c.1603C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg535Trp (c.1603C>T) in the general population?

EPHB4 p.Arg535Trp (c.1603C>T) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about EPHB4 p.Arg535Trp (c.1603C>T)?

AlphaMissense predicts likely benign (score 0.2621) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg535Trp

c.1603C>T · rs778356891 · VCV1776220

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2621 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2621	likely benign
REVEL	0.512	indeterminate
SaProt	LLR -8.71	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 1.7	GERP 0.09, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	26.7	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 0.148% Middle Eastern · 9/6,084 alleles

Filtering AF 0.0772% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0576%

Overall 0.00496% 80/1,613,924 alleles · rare exomes 75/1,461,766 · genomes 5/152,158 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	676
South Asian	0.00769%	13,011
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00475%	21,071
Admixed American	0.00333%	29,993
African / African-American	0.00267%	37,460

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.Arg535Trp
Coding: c.1603C>T
MANE Select: NM_004444
dbSNP: rs778356891
Type: single nucleotide variant
Location: chr7:100814007 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 535: a UniProt-annotated variant site (in cmavm2)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 c.1870+5G>C Uncertain significance ★★ same condition
EPHB4 p.Ala262Val Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala345Gly Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala931Thr Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg148Trp Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg310Gln Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg483Gln Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg499Gln 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/ephb4-p-arg535trp (accessed [today's date]).

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