Is EPHB4 p.Pro346= (c.1038C>G) pathogenic?

EPHB4 p.Pro346= (c.1038C>G) is classified Likely benign in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-10). Very rare (popmax 0.00241%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Pro346= (c.1038C>G)?

EPHB4 p.Pro346= (c.1038C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Pro346= (c.1038C>G) in the general population?

EPHB4 p.Pro346= (c.1038C>G) is very rare (popmax 0.00241%, eas) (gnomAD).

EPHB4 p.Pro346=

c.1038C>G · rs781490021 · VCV1773130

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00241%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.72	GERP -5, phastCons 0.001
Overall
CADD	4.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00241% East Asian · 1/41,514 alleles

Filtering AF 0.000298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000216%

Overall 0.000705% 11/1,560,890 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00241%	41,514
Remaining individualsnot grpmax-eligible	0.00165%	60,496
South Asian	0.00117%	85,756
European (non-Finnish)	0.000694%	144,126

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.Pro346=
Coding: c.1038C>G
MANE Select: NM_004444
dbSNP: rs781490021
Type: single nucleotide variant
Location: chr7:100819816 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 346: a UniProt-annotated variant site (in cmavm2); a UniProt-annotated variant site (in a metastatic melanoma sample; somatic mutation); the fibronectin type-iii 1 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 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-pro346 (accessed [today's date]).

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