Is EPHB4 p.Thr544Met (c.1631C>T) pathogenic?

EPHB4 p.Thr544Met (c.1631C>T) is classified Likely benign in EPHB4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-01). AlphaMissense: likely benign (0.2104); Ultra-rare (popmax 0.0174%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Thr544Met (c.1631C>T)?

EPHB4 p.Thr544Met (c.1631C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Thr544Met (c.1631C>T) in the general population?

EPHB4 p.Thr544Met (c.1631C>T) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about EPHB4 p.Thr544Met (c.1631C>T)?

AlphaMissense predicts likely benign (score 0.2104) — an in-silico prediction, not a clinical call.

EPHB4 p.Thr544Met

c.1631C>T · rs766417205 · VCV1776838

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2104 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2104	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -7.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	23.8	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 0.0174% African / African-American · 13/74,918 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00204% 33/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,763
Admixed American	0.01%	10,000
Finnishnot grpmax-eligible	0.00625%	16,001
Remaining individualsnot grpmax-eligible	0.0016%	62,482
South Asian	0.0011%	91,082
European (non-Finnish)	0.000678%	147,506

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.Thr544Met
Coding: c.1631C>T
MANE Select: NM_004444
dbSNP: rs766417205
Type: single nucleotide variant
Location: chr7:100813979 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 544: a UniProt-annotated variant site (in cmavm2)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 p.Thr544= Benign/Likely benign ★★ same residue
EPHB4 c.1870+5G>C Uncertain significance ★★ same condition
EPHB4 p.Ala262Val Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala345Gly Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala931Thr Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg148Trp Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg310Gln Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg483Gln 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-thr544met (accessed [today's date]).

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