Is EPHB4 p.Arg206Gly (c.616C>G) pathogenic?

EPHB4 p.Arg206Gly (c.616C>G) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-19). AlphaMissense: likely benign (0.1454); Very rare (popmax 0.000425%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg206Gly (c.616C>G)?

EPHB4 p.Arg206Gly (c.616C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg206Gly (c.616C>G) in the general population?

EPHB4 p.Arg206Gly (c.616C>G) is very rare (popmax 0.000425%, nfe) (gnomAD).

What do computational predictors say about EPHB4 p.Arg206Gly (c.616C>G)?

AlphaMissense predicts likely benign (score 0.1454) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg206Gly

c.616C>G · VCV3275977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1454 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1454	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -9.39	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 2.1	GERP -4.1, phastCons 0.94
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	14.25	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 0.000425% European (non-Finnish) · 5/1,176,102 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000311% 5/1,608,418 alleles · very rare

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.Arg206Gly
Coding: c.616C>G
MANE Select: NM_004444
Type: single nucleotide variant
Location: chr7:100822463 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 206: 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 p.Arg206Ter Pathogenic ★ same residue
EPHB4 p.Arg206= Likely benign ★ same residue
EPHB4 p.Arg206Gln 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

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-arg206gly (accessed [today's date]).

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