Is EPHB1 p.Phe552Leu (c.1656C>G) pathogenic?

EPHB1 p.Phe552Leu (c.1656C>G) is classified Uncertain significance in EPHB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely pathogenic (0.8229); Very rare (popmax 0.000339%, nfe).

How common is EPHB1 p.Phe552Leu (c.1656C>G) in the general population?

EPHB1 p.Phe552Leu (c.1656C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EPHB1 p.Phe552Leu (c.1656C>G)?

AlphaMissense predicts likely pathogenic (score 0.8229) — an in-silico prediction, not a clinical call.

EPHB1 p.Phe552Leu

c.1656C>G · rs56372452 · VCV2405185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8229	likely pathogenic
REVEL	0.257	benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -5.2
Regional constraint	o/e 0.81	unconstrained · MANE · 463 kb · p 2.5e-12 · regional, not allelic
Overall
CADD	8.574	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 0.000339% European (non-Finnish) · 4/1,179,852 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,664 alleles · very rare

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.Phe552Leu
Coding: c.1656C>G
MANE Select: NM_004441
dbSNP: rs56372452
Type: single nucleotide variant
Location: chr3:135166038 (GRCh38)
Gene constraint: LOEUF 0.441 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.95 · 8 PDB

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

Similar variants

EPHB1 p.Phe552= Benign/Likely benign ★★ same residue
EPHB1 p.Ile561= 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-phe552leu (accessed [today's date]).

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