Is EPHB1 p.Pro420Ala (c.1258C>G) pathogenic?

EPHB1 p.Pro420Ala (c.1258C>G) is classified Uncertain significance in EPHB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-21). AlphaMissense: likely benign (0.0834); Very rare (popmax 0.00896%, eas).

How common is EPHB1 p.Pro420Ala (c.1258C>G) in the general population?

EPHB1 p.Pro420Ala (c.1258C>G) is very rare (popmax 0.00896%, eas) (gnomAD).

What do computational predictors say about EPHB1 p.Pro420Ala (c.1258C>G)?

AlphaMissense predicts likely benign (score 0.0834) — an in-silico prediction, not a clinical call.

EPHB1 p.Pro420Ala

c.1258C>G · VCV3275958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0834 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00896%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0834	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -9.07	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 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 463 kb · p 2.5e-12 · regional, not allelic
Overall
CADD	18.42	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 0.00896% East Asian · 4/44,628 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00181%

Overall 0.000436% 7/1,605,042 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00896%	11,157
Remaining individualsnot grpmax-eligible	0.00161%	62,052
European (non-Finnish)	0.000171%	586,424

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: EPHB1
Protein: p.Pro420Ala
Coding: c.1258C>G
MANE Select: NM_004441
Type: single nucleotide variant
Location: chr3:135133010 (GRCh38)
Gene constraint: LOEUF 0.441 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.95 · 8 PDB
Residue 420: the fibronectin type-iii 1 domain

Full EPHB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB1 p.Ile561= Benign ★★ same type
EPHB1 p.Phe552= Benign/Likely benign ★★ same type
EPHB1 p.Thr981= Benign ★★ same type
EPHB1 c.2347-1G>A Uncertain significance ★ same type
EPHB1 p.Ala12Ser Uncertain significance ★ ⚠ same type
EPHB1 p.Ala132Gly Uncertain significance ★ ⚠ same type
EPHB1 p.Ala182Thr Uncertain significance ★ ⚠ same type
EPHB1 p.Ala39Val Uncertain significance ★ ⚠ 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/ephb1-p-pro420ala (accessed [today's date]).

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