Is EPHB4 p.Arg444Trp (c.1330C>T) pathogenic?

EPHB4 p.Arg444Trp (c.1330C>T) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-13). AlphaMissense: likely benign (0.229); Very rare (popmax 0.005%, amr).

How common is EPHB4 p.Arg444Trp (c.1330C>T) in the general population?

EPHB4 p.Arg444Trp (c.1330C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Arg444Trp (c.1330C>T)?

AlphaMissense predicts likely benign (score 0.229) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg444Trp

c.1330C>T · rs370505170 · VCV811866

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.229	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -9.90	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 1.9	GERP -4.1, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,984 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00205% 33/1,612,628 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,995
South Asian	0.00329%	30,354
African / African-American	0.00266%	37,525
East Asian	0.00223%	44,876
European (non-Finnish)	0.00195%	51,303
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Arg444Trp
Coding: c.1330C>T
MANE Select: NM_004444
dbSNP: rs370505170
Type: single nucleotide variant
Location: chr7:100818612 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 444: a β-strand; a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 2 domain

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

Similar variants

EPHB4 p.Arg444Leu Likely benign ★ same residue
EPHB4 c.1691+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg394Ter Pathogenic ★★ same type
EPHB4 p.Arg431Ter Pathogenic ★★ same type
EPHB4 p.Arg739Gln Pathogenic ★★ same type

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-arg444trp (accessed [today's date]).

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