Is EPHB4 p.Glu432Val (c.1295A>T) pathogenic?

EPHB4 p.Glu432Val (c.1295A>T) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-23). AlphaMissense: ambiguous (0.4192); Absent from gnomAD v4.1.

How common is EPHB4 p.Glu432Val (c.1295A>T) in the general population?

EPHB4 p.Glu432Val (c.1295A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHB4 p.Glu432Val (c.1295A>T)?

AlphaMissense predicts ambiguous (score 0.4192) — an in-silico prediction, not a clinical call.

EPHB4 p.Glu432Val

c.1295A>T · rs2485035382 · VCV2010774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4192 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4192	ambiguous
REVEL	0.096	moderately benign-leaning
SaProt	LLR -6.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.31	donor gain · deltas
Pangolin	Δ0.48	gain · loss 0.16 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP -2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	29.3	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

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.Glu432Val
Coding: c.1295A>T
MANE Select: NM_004444
dbSNP: rs2485035382
Type: single nucleotide variant
Location: chr7:100819559 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 432: a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 1 domain

Full EPHB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB4 p.Glu432Asp 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
EPHB4 p.Arg739Gln 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-glu432val (accessed [today's date]).

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