Is EPHB4 p.Gln537His (c.1611G>C) pathogenic?

EPHB4 p.Gln537His (c.1611G>C) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-16). AlphaMissense: ambiguous (0.4058); Very rare (popmax 0.004%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Gln537His (c.1611G>C)?

EPHB4 p.Gln537His (c.1611G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Gln537His (c.1611G>C) in the general population?

EPHB4 p.Gln537His (c.1611G>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about EPHB4 p.Gln537His (c.1611G>C)?

AlphaMissense predicts ambiguous (score 0.4058) — an in-silico prediction, not a clinical call.

EPHB4 p.Gln537His

c.1611G>C · VCV3275979

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4058	ambiguous
REVEL	0.406	indeterminate
SaProt	LLR -6.56	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.17, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	23.5	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 0.004% African / African-American · 3/75,062 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.00197% 3/152,320 alleles · very rare

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.Gln537His
Coding: c.1611G>C
MANE Select: NM_004444
Type: single nucleotide variant
Location: chr7:100813999 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 537: 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.Gln537= Likely benign ★ same residue
EPHB4 p.Gln537Ter Pathogenic/Likely pathogenic ★★ 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

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-gln537his (accessed [today's date]).

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