Is EPHB4 p.Arg483Gln (c.1448G>A) pathogenic?

EPHB4 p.Arg483Gln (c.1448G>A) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-23). AlphaMissense: likely benign (0.0968); Ultra-rare (popmax 0.015%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg483Gln (c.1448G>A)?

EPHB4 p.Arg483Gln (c.1448G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg483Gln (c.1448G>A) in the general population?

EPHB4 p.Arg483Gln (c.1448G>A) is ultra-rare (popmax 0.015%, sas) (gnomAD).

What do computational predictors say about EPHB4 p.Arg483Gln (c.1448G>A)?

AlphaMissense predicts likely benign (score 0.0968) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg483Gln

c.1448G>A · rs780234148 · VCV1772840

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0968 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0968	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -7.58	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 3.9	GERP 1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.015% South Asian · 13/86,688 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00702%

Overall 0.00385% 61/1,582,838 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.015%	6,668
African / African-American	0.0149%	6,716
East Asian	0.00464%	21,542
European (non-Finnish)	0.00283%	35,324
Admixed American	0.00178%	56,094
Remaining individualsnot grpmax-eligible	0.00163%	61,180

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.Arg483Gln
Coding: c.1448G>A
MANE Select: NM_004444
dbSNP: rs780234148
Type: single nucleotide variant
Location: chr7:100817332 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 483: a β-strand; a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 2 domain

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 p.Arg483Trp Uncertain significance ★ ⚠ same residue
EPHB4 p.Arg483= Likely benign ★ same residue
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

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-arg483gln (accessed [today's date]).

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