Is EPHB4 p.Ser294Cys (c.881C>G) pathogenic?

EPHB4 p.Ser294Cys (c.881C>G) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-11). AlphaMissense: likely pathogenic (0.6692); Ultra-rare (popmax 0.0133%, amr).

How common is EPHB4 p.Ser294Cys (c.881C>G) in the general population?

EPHB4 p.Ser294Cys (c.881C>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Ser294Cys (c.881C>G)?

AlphaMissense predicts likely pathogenic (score 0.6692) — an in-silico prediction, not a clinical call.

EPHB4 p.Ser294Cys

c.881C>G · rs759058404 · VCV2883851

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6692	likely pathogenic
REVEL	0.203	benign-leaning
SaProt	LLR -11.78	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	26.4	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 0.0133% Admixed American · 8/59,996 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000558% 9/1,614,040 alleles · ultra-rare exomes 8/1,461,848 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Ser294Cys
Coding: c.881C>G
MANE Select: NM_004444
dbSNP: rs759058404
Type: single nucleotide variant
Location: chr7:100820224 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 294: a UniProt-annotated variant site (in cmavm2)

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

Similar variants

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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
EPHB4 p.Arg739Ter 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-ser294cys (accessed [today's date]).

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