Is EPHB6 p.Arg66Gln (c.197G>A) pathogenic?

EPHB6 p.Arg66Gln (c.197G>A) is classified Uncertain significance in EPHB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). Very rare (popmax 0.00267%, afr).

How common is EPHB6 p.Arg66Gln (c.197G>A) in the general population?

EPHB6 p.Arg66Gln (c.197G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

EPHB6 p.Arg66Gln

c.197G>A · VCV4664803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -1.6, phastCons 1
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,934 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00211% 34/1,614,082 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,467
European (non-Finnish)	0.00237%	42,144
East Asian	0.00223%	44,890
South Asian	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg66Gln
Coding: c.197G>A
MANE Select: NM_004445
Type: single nucleotide variant
Location: chr7:142863997 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.36 · 1 PDB
Residue 66: a β-strand; the eph lbd domain

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

Similar variants

EPHB6 p.Arg66Pro Uncertain significance same residue
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

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-arg66gln (accessed [today's date]).

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