Is EPHB4 p.Asn265Ser (c.794A>G) pathogenic?

EPHB4 p.Asn265Ser (c.794A>G) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-04). AlphaMissense: likely benign (0.0849); Ultra-rare (popmax 0.0164%, afr).

How common is EPHB4 p.Asn265Ser (c.794A>G) in the general population?

EPHB4 p.Asn265Ser (c.794A>G) is ultra-rare (popmax 0.0164%, afr) (gnomAD).

What do computational predictors say about EPHB4 p.Asn265Ser (c.794A>G)?

AlphaMissense predicts likely benign (score 0.0849) — an in-silico prediction, not a clinical call.

EPHB4 p.Asn265Ser

c.794A>G · rs889890364 · VCV1929685

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0849 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0849	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	17.07	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 0.0164% African / African-American · 12/73,388 alleles

Filtering AF 0.00939% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.000896% 14/1,562,298 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0164%	6,116
European (non-Finnish)	0.000174%	576,229

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.Asn265Ser
Coding: c.794A>G
MANE Select: NM_004444
dbSNP: rs889890364
Type: single nucleotide variant
Location: chr7:100822285 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 265: 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
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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-asn265ser (accessed [today's date]).

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