Is EPHB4 p.Arg866His (c.2597G>A) pathogenic?

EPHB4 p.Arg866His (c.2597G>A) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-05). AlphaMissense: likely benign (0.1671); Very rare (popmax 0.00859%, sas); Associated with EPHB4-related disorder.

What condition is associated with EPHB4 p.Arg866His (c.2597G>A)?

EPHB4 p.Arg866His (c.2597G>A) is associated with EPHB4-related disorder (ClinVar).

How common is EPHB4 p.Arg866His (c.2597G>A) in the general population?

EPHB4 p.Arg866His (c.2597G>A) is very rare (popmax 0.00859%, sas) (gnomAD).

What do computational predictors say about EPHB4 p.Arg866His (c.2597G>A)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg866His

c.2597G>A · rs549742543 · VCV2629283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00859%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

EPHB4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP -0.92, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · regional, not allelic
Overall
CADD	32.0	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 0.00859% South Asian · 7/81,512 alleles

Filtering AF 0.00396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00123% 19/1,550,002 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00859%	11,645
Finnishnot grpmax-eligible	0.00321%	31,126
European (non-Finnish)	0.00087%	114,939

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.Arg866His
Coding: c.2597G>A
MANE Select: NM_004444
dbSNP: rs549742543
Type: single nucleotide variant
Location: chr7:100805582 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 866: a UniProt-annotated variant site (in cmavm2); the protein kinase domain

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

Disease context

EPHB4-related disorder

Similar variants

EPHB4 c.1691+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg785Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Gln537Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Leu494Pro Likely pathogenic ★★ same condition
EPHB4 p.Trp72Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Pro983Leu Uncertain significance ★★ ⚠ same condition
EPHB4 c.1422+1G>A 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-arg866his (accessed [today's date]).

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