Is EPHB4 p.Arg564Ser (c.1692G>C) pathogenic?

EPHB4 p.Arg564Ser (c.1692G>C) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-01). AlphaMissense: likely pathogenic (0.6583); Ultra-rare (popmax 0.0165%, mid); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg564Ser (c.1692G>C)?

EPHB4 p.Arg564Ser (c.1692G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg564Ser (c.1692G>C) in the general population?

EPHB4 p.Arg564Ser (c.1692G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about EPHB4 p.Arg564Ser (c.1692G>C)?

AlphaMissense predicts likely pathogenic (score 0.6583) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg564Ser

c.1692G>C · VCV3340438

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6583 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6583	likely pathogenic
REVEL	0.246	benign-leaning
SaProt	LLR -11.12	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	27.3	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00123% 18/1,461,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-American	0.00133%	75,056
European (non-Finnish)	0.00127%	78,670

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.Arg564Ser
Coding: c.1692G>C
MANE Select: NM_004444
Type: single nucleotide variant
Location: chr7:100813716 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 564: 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 p.Arg564Thr Uncertain significance ★★ ⚠ same residue
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

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-arg564ser (accessed [today's date]).

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