Is EPHB6 p.Arg861Trp (c.2581C>T) pathogenic?

EPHB6 p.Arg861Trp (c.2581C>T) is classified Uncertain significance in EPHB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). Very rare (popmax 0.00508%, nfe).

How common is EPHB6 p.Arg861Trp (c.2581C>T) in the general population?

EPHB6 p.Arg861Trp (c.2581C>T) is very rare (popmax 0.00508%, nfe) (gnomAD).

EPHB6 p.Arg861Trp

c.2581C>T · VCV4249985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00508%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.601	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.88, phastCons 1
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00508% European (non-Finnish) · 60/1,180,026 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00421% 68/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,006
European (non-Finnish)grpmax	0.00508%	19,667
East Asian	0.00223%	44,890
Admixed American	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,078

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg861Trp
Coding: c.2581C>T
MANE Select: NM_004445
Type: single nucleotide variant
Location: chr7:142869937 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.36 · 1 PDB
Residue 861: the protein kinase domain

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-arg861trp (accessed [today's date]).

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