Is EPHB2 p.Ser426Cys (c.1277C>G) pathogenic?

EPHB2 p.Ser426Cys (c.1277C>G) is classified Uncertain significance in EPHB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.5759); Absent from gnomAD v4.1.

How common is EPHB2 p.Ser426Cys (c.1277C>G) in the general population?

EPHB2 p.Ser426Cys (c.1277C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHB2 p.Ser426Cys (c.1277C>G)?

AlphaMissense predicts likely pathogenic (score 0.5759) — an in-silico prediction, not a clinical call.

EPHB2 p.Ser426Cys

c.1277C>G · VCV4249926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5759 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5759	likely pathogenic
REVEL	0.462	indeterminate
SaProt	LLR -13.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 203 kb · p 2.4e-23 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPHB2
Protein: p.Ser426Cys
Coding: c.1277C>G
MANE Select: NM_017449
Type: single nucleotide variant
Location: chr1:22865186 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 5 PDB
Residue 426: the fibronectin type-iii 1 domain

Full EPHB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB2 p.Val414Ile Uncertain significance ★★ ⚠ same type
EPHB2 c.1766-9G>T Benign/Likely benign ★★ same type
EPHB2 p.Ala279Ser Benign ★★ same type
EPHB2 p.Asn242= Likely benign ★★ same type
EPHB2 p.Asp574= Benign ★★ same type
EPHB2 p.Asp678Asn Likely benign ★★ ⚠ same type
EPHB2 p.Gln875= Benign ★★ same type
EPHB2 p.Ser170= Benign ★★ 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/ephb2-p-ser426cys (accessed [today's date]).

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