Is EPHB4 p.Glu790Ala (c.2369A>C) pathogenic?

EPHB4 p.Glu790Ala (c.2369A>C) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-05). AlphaMissense: likely pathogenic (0.9966); Absent from gnomAD v4.1.

How common is EPHB4 p.Glu790Ala (c.2369A>C) in the general population?

EPHB4 p.Glu790Ala (c.2369A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHB4 p.Glu790Ala (c.2369A>C)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

EPHB4 p.Glu790Ala

c.2369A>C · rs780716438 · VCV1046952

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic · top 9% in EPHB4
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -15.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 6,734 bp · p 5.4e-12 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPHB4
Protein: p.Glu790Ala
Coding: c.2369A>C
MANE Select: NM_004444
dbSNP: rs780716438
Type: single nucleotide variant
Location: chr7:100806535 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 790: an α-helix; 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

Similar variants

EPHB4 p.Glu790Asp Uncertain significance ★ ⚠ same residue
EPHB4 p.Glu790Lys Uncertain significance ★ ⚠ same residue
EPHB4 c.1691+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg394Ter Pathogenic ★★ same type
EPHB4 p.Arg431Ter Pathogenic ★★ same type

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-glu790ala (accessed [today's date]).

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