Is EPHB4 p.Pro841Leu (c.2522C>T) pathogenic?

EPHB4 p.Pro841Leu (c.2522C>T) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-04-18). AlphaMissense: likely pathogenic (0.5937); Very rare (popmax 0.00223%, amr); Associated with lymphatic malformation 7.

What condition is associated with EPHB4 p.Pro841Leu (c.2522C>T)?

EPHB4 p.Pro841Leu (c.2522C>T) is associated with lymphatic malformation 7 (ClinVar).

How common is EPHB4 p.Pro841Leu (c.2522C>T) in the general population?

EPHB4 p.Pro841Leu (c.2522C>T) is very rare (popmax 0.00223%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Pro841Leu (c.2522C>T)?

AlphaMissense predicts likely pathogenic (score 0.5937) — an in-silico prediction, not a clinical call.

EPHB4 p.Pro841Leu

c.2522C>T · rs763645511 · VCV2521643

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

lymphatic malformation 7

Computational evidence

Protein change
AlphaMissense	0.5937	likely pathogenic
REVEL	0.62	indeterminate
SaProt	LLR -11.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · regional, not allelic
Overall
CADD	33.0	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 0.00223% Admixed American · 1/44,892 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00169% 26/1,535,038 alleles · very rare exomes 21/1,382,848 · genomes 5/152,190 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00339%	29,490
Admixed Americangrpmax	0.00223%	44,892
European (non-Finnish)	0.00192%	51,970
South Asian	0.00127%	78,762

Remaining individuals 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.Pro841Leu
Coding: c.2522C>T
MANE Select: NM_004444
dbSNP: rs763645511
Type: single nucleotide variant
Location: chr7:100805657 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 841: an α-helix; 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

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

Similar variants

EPHB4 p.Pro841= Likely benign ★★ same residue
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg739Gln Pathogenic ★★ same condition
EPHB4 p.Gln580Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Ser280Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Lys859Arg Uncertain significance ★★ ⚠ same condition
EPHB4 p.Met728Val Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ser299Leu 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-pro841leu (accessed [today's date]).

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