Is EPHB4 p.Val612Ala (c.1835T>C) pathogenic?

EPHB4 p.Val612Ala (c.1835T>C) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-02). AlphaMissense: likely benign (0.2499); Ultra-rare (popmax 0.0121%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Val612Ala (c.1835T>C)?

EPHB4 p.Val612Ala (c.1835T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Val612Ala (c.1835T>C) in the general population?

EPHB4 p.Val612Ala (c.1835T>C) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about EPHB4 p.Val612Ala (c.1835T>C)?

AlphaMissense predicts likely benign (score 0.2499) — an in-silico prediction, not a clinical call.

EPHB4 p.Val612Ala

c.1835T>C · VCV4842538

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2499 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2499	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 6,734 bp · p 5.4e-12 · regional, not allelic
Overall
CADD	22.6	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 0.0121% South Asian · 11/91,084 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000806% 13/1,612,620 alleles · ultra-rare exomes 10/1,460,410 · genomes 3/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,280
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	8.47e-05%	1,180,004

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.Val612Ala
Coding: c.1835T>C
MANE Select: NM_004444
Type: single nucleotide variant
Location: chr7:100813130 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 612: an α-helix; 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 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
EPHB4 p.Arg483Gln Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg499Gln 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-val612ala (accessed [today's date]).

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