Is EPHB4 p.Cys630= (c.1890C>T) pathogenic?

EPHB4 p.Cys630= (c.1890C>T) is classified Benign in EPHB4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 39%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with capillary malformation-arteriovenous malformation 2.

EPHB4 p.Cys630=

Q: What condition is associated with EPHB4 p.Cys630= (c.1890C>T)?

EPHB4 p.Cys630= (c.1890C>T) is associated with capillary malformation-arteriovenous malformation 2, lymphatic malformation 7 (ClinVar).

Q: How common is EPHB4 p.Cys630= (c.1890C>T) in the general population?

EPHB4 p.Cys630= (c.1890C>T) is common (popmax 39%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1890C>T · rs2230585 · VCV811000

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 39%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

capillary malformation-arteriovenous malformation 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.27, phastCons 1
Overall
CADD	9.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 39% European (non-Finnish) · 459,939/1,179,852 alleles

Filtering AF 38.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 38.8%

Overall 36.7% 592,583/1,613,700 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	43.8%	2
Finnishnot grpmax-eligible	42.2%	2
European (non-Finnish)grpmax	39%	3
Amishnot grpmax-eligible	36.7%	3
Remaining individualsnot grpmax-eligible	36.2%	3
East Asian	29.7%	3
Admixed American	27.8%	4
Middle Eastern	27.1%	4
South Asian	25.8%	4
African / African-American	19.4%	5

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys630=
Coding: c.1890C>T
MANE Select: NM_004444
dbSNP: rs2230585
Type: single nucleotide variant
Location: chr7:100812975 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 630: a β-strand; 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

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-cys630 (accessed [today's date]).

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