Is EPHB4 p.Arg102Trp (c.304C>T) pathogenic?

EPHB4 p.Arg102Trp (c.304C>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). AlphaMissense: likely benign (0.1779); Very rare (popmax 0.00446%, eas).

How common is EPHB4 p.Arg102Trp (c.304C>T) in the general population?

EPHB4 p.Arg102Trp (c.304C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about EPHB4 p.Arg102Trp (c.304C>T)?

AlphaMissense predicts likely benign (score 0.1779) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg102Trp

c.304C>T · rs141985925 · VCV2964100

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1779 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1779	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.86	GERP -2.9
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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,874 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00062% 10/1,613,622 alleles · very rare exomes 9/1,461,250 · genomes 1/152,372 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,437
South Asian	0.00329%	30,364
Finnishnot grpmax-eligible	0.00157%	63,518
African / African-American	0.00133%	75,068
European (non-Finnish)	0.000254%	393,321

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.Arg102Trp
Coding: c.304C>T
MANE Select: NM_004444
dbSNP: rs141985925
Type: single nucleotide variant
Location: chr7:100823751 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 102: the eph lbd domain

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

Similar variants

EPHB4 p.Arg102Gln Uncertain significance ★ ⚠ 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-arg102trp (accessed [today's date]).

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