Is EPHB4 p.Pro208Leu (c.623C>T) pathogenic?

EPHB4 p.Pro208Leu (c.623C>T) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.2079); Rare (popmax 0.189%, afr); Associated with lymphatic malformation 7.

What condition is associated with EPHB4 p.Pro208Leu (c.623C>T)?

EPHB4 p.Pro208Leu (c.623C>T) is associated with lymphatic malformation 7, capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Pro208Leu (c.623C>T) in the general population?

EPHB4 p.Pro208Leu (c.623C>T) is rare (popmax 0.189%, afr) (gnomAD).

What do computational predictors say about EPHB4 p.Pro208Leu (c.623C>T)?

AlphaMissense predicts likely benign (score 0.2079) — an in-silico prediction, not a clinical call.

EPHB4 p.Pro208Leu

c.623C>T · rs111749768 · VCV2062638

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2079 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.189%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphatic malformation 7

Computational evidence

Protein change
AlphaMissense	0.2079	likely benign
REVEL	0.769	pathogenic-leaning
SaProt	LLR -12.27	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	31.0	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 0.189% African / African-American · 142/74,962 alleles

Filtering AF 0.164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.154%

Overall 0.0103% 166/1,607,744 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.189%	528
South Asian	0.00771%	12,963
Admixed American	0.0067%	14,929
Remaining individualsnot grpmax-eligible	0.00482%	20,728
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,398
European (non-Finnish)	0.000765%	130,636

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.Pro208Leu
Coding: c.623C>T
MANE Select: NM_004444
dbSNP: rs111749768
Type: single nucleotide variant
Location: chr7:100822456 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 208: a UniProt-annotated variant site (in cmavm2)

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

Disease context

lymphatic malformation 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: capillary malformation-arteriovenous malformation 2

Similar variants

EPHB4 p.Pro208= Likely benign ★★ same residue
EPHB4 p.Pro208Gln Uncertain significance ★ ⚠ same residue
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

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-pro208leu (accessed [today's date]).

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