Is EPHB4 p.Pro843Arg (c.2528C>G) pathogenic?

EPHB4 p.Pro843Arg (c.2528C>G) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-25). AlphaMissense: ambiguous (0.4115); Very rare (popmax 0.0022%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Pro843Arg (c.2528C>G)?

EPHB4 p.Pro843Arg (c.2528C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Pro843Arg (c.2528C>G) in the general population?

EPHB4 p.Pro843Arg (c.2528C>G) is very rare (popmax 0.0022%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Pro843Arg (c.2528C>G)?

AlphaMissense predicts ambiguous (score 0.4115) — an in-silico prediction, not a clinical call.

EPHB4 p.Pro843Arg

c.2528C>G · VCV3275991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4115	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -7.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP -2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · regional, not allelic
Overall
CADD	27.1	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 0.0022% Admixed American · 1/45,382 alleles

Overall 0.000144% 2/1,387,936 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0022%	45,382
Remaining individualsnot grpmax-eligible	0.00169%	59,250

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.Pro843Arg
Coding: c.2528C>G
MANE Select: NM_004444
Type: single nucleotide variant
Location: chr7:100805651 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 843: a UniProt-annotated variant site (in cmavm2); the protein kinase domain

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.Pro843= Likely benign ★ 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-pro843arg (accessed [today's date]).

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