Is EPHB4 p.Pro820Thr (c.2458C>A) pathogenic?

EPHB4 p.Pro820Thr (c.2458C>A) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-29). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with capillary malformation-arteriovenous malformation 2.

What condition is associated with EPHB4 p.Pro820Thr (c.2458C>A)?

EPHB4 p.Pro820Thr (c.2458C>A) is associated with capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Pro820Thr (c.2458C>A) in the general population?

EPHB4 p.Pro820Thr (c.2458C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHB4 p.Pro820Thr (c.2458C>A)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

EPHB4 p.Pro820Thr

c.2458C>A · rs1584653653 · VCV691547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation 2

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 2% in EPHB4
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -12.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · regional, not allelic
Overall
CADD	31.0	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.Pro820Thr
Coding: c.2458C>A
MANE Select: NM_004444
dbSNP: rs1584653653
Type: single nucleotide variant
Location: chr7:100806446 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 820: a turn; a UniProt-annotated variant site (in cmavm2); a UniProt-annotated variant site (in cmavm2; uncertain significance); the protein kinase domain

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

Disease context

capillary malformation-arteriovenous malformation 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 p.Pro820Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EPHB4 p.Pro820Gln Uncertain significance ★ ⚠ same residue
EPHB4 p.Pro820Ser Uncertain significance ★ ⚠ same residue
EPHB4 p.Pro820= Likely benign ★ same residue
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg739Ter Pathogenic ★★ same condition
EPHB4 p.Arg763Ter Pathogenic/Likely pathogenic ★★ 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-pro820thr (accessed [today's date]).

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