Is EPHB4 p.Val84Ile (c.250G>A) pathogenic?

EPHB4 p.Val84Ile (c.250G>A) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-12-12). AlphaMissense: likely benign (0.0897); Ultra-rare (popmax 0.0165%, mid); Associated with capillary malformation-arteriovenous malformation 2.

How common is EPHB4 p.Val84Ile (c.250G>A) in the general population?

EPHB4 p.Val84Ile (c.250G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about EPHB4 p.Val84Ile (c.250G>A)?

AlphaMissense predicts likely benign (score 0.0897) — an in-silico prediction, not a clinical call.

EPHB4 p.Val84Ile

Q: What condition is associated with EPHB4 p.Val84Ile (c.250G>A)?

EPHB4 p.Val84Ile (c.250G>A) is associated with capillary malformation-arteriovenous malformation 2, lymphatic malformation 7 (ClinVar).

c.250G>A · rs201465765 · VCV1792379

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0897 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation 2

Computational evidence

Protein change
AlphaMissense	0.0897	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -3.1, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	17.23	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00124% 20/1,613,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
East Asian	0.00446%	22,439
South Asian	0.00329%	30,356
Remaining individualsnot grpmax-eligible	0.0032%	31,235
Finnishnot grpmax-eligible	0.00158%	63,266
African / African-American	0.00133%	75,058
European (non-Finnish)	0.000848%	117,991

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.Val84Ile
Coding: c.250G>A
MANE Select: NM_004444
dbSNP: rs201465765
Type: single nucleotide variant
Location: chr7:100823805 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 84: a disulfide bond; the eph lbd domain; a β-strand

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

Also linked: lymphatic malformation 7

Similar variants

EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg739Gln Pathogenic ★★ same condition
EPHB4 p.Arg739Ter Pathogenic ★★ same condition
EPHB4 p.Arg763Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Gln580Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Glu664Lys Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Ser280Ter 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-val84ile (accessed [today's date]).

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