Is EPHB6 p.Pro456Thr (c.1366C>A) pathogenic?

EPHB6 p.Pro456Thr (c.1366C>A) is classified Uncertain significance in EPHB6 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-04). Very rare (popmax 0.00446%, eas).

How common is EPHB6 p.Pro456Thr (c.1366C>A) in the general population?

EPHB6 p.Pro456Thr (c.1366C>A) is very rare (popmax 0.00446%, eas) (gnomAD).

EPHB6 p.Pro456Thr

c.1366C>A · VCV4334342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.072	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -0.28, phastCons 1
Overall
CADD	18.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000205% 3/1,461,840 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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: EPHB6
Protein: p.Pro456Thr
Coding: c.1366C>A
MANE Select: NM_004445
Type: single nucleotide variant
Location: chr7:142866220 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.36 · 1 PDB
Residue 456: the fibronectin type-iii 1 domain; a β-strand

Full EPHB6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPV6 p.Arg390Cys Uncertain significance ★★ ⚠ same type
EPHB6 p.Arg905Gln Likely benign ★★ same type
EPHB6 p.Ala341Pro Uncertain significance ★ same type
EPHB6 p.Ala341Ser Uncertain significance ★ same type
EPHB6 p.Ala341Thr Uncertain significance ★ same type
EPHB6 p.Ala453Ser Uncertain significance ★ same type
EPHB6 p.Ala567Val Uncertain significance ★ same type
EPHB6 p.Ala617Gly 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/ephb6-p-pro456thr (accessed [today's date]).

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