Is EPHB4 p.Ser299Leu (c.896C>T) pathogenic?

EPHB4 p.Ser299Leu (c.896C>T) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-14). AlphaMissense: likely benign (0.2293); Very rare (popmax 0.00833%, amr); Associated with lymphatic malformation 7.

What condition is associated with EPHB4 p.Ser299Leu (c.896C>T)?

EPHB4 p.Ser299Leu (c.896C>T) is associated with lymphatic malformation 7 (ClinVar).

How common is EPHB4 p.Ser299Leu (c.896C>T) in the general population?

EPHB4 p.Ser299Leu (c.896C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Ser299Leu (c.896C>T)?

AlphaMissense predicts likely benign (score 0.2293) — an in-silico prediction, not a clinical call.

EPHB4 p.Ser299Leu

c.896C>T · rs964985310 · VCV2981375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lymphatic malformation 7

Computational evidence

Protein change
AlphaMissense	0.2293	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -10.58	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 8.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	24.6	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 0.00833% Admixed American · 5/60,020 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000342% 5/1,461,848 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.Ser299Leu
Coding: c.896C>T
MANE Select: NM_004444
dbSNP: rs964985310
Type: single nucleotide variant
Location: chr7:100820209 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 299: 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

Similar variants

EPHB4 p.Ser299Ter Pathogenic/Likely pathogenic ★★ 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 c.1422+3A>G Benign ★★ 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-ser299leu (accessed [today's date]).

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