Is EPHB6 p.Arg391His (c.1172G>A) pathogenic?

EPHB6 p.Arg391His (c.1172G>A) is classified Uncertain significance in EPHB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). Ultra-rare (popmax 0.0134%, eas).

How common is EPHB6 p.Arg391His (c.1172G>A) in the general population?

EPHB6 p.Arg391His (c.1172G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

EPHB6 p.Arg391His

c.1172G>A · VCV3509433

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.208	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,848 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00428% 69/1,613,582 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,475
South Asian	0.00769%	12,997
European (non-Finnish)	0.00449%	22,261
Admixed American	0.00167%	59,964
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00133%	75,048

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.Arg391His
Coding: c.1172G>A
MANE Select: NM_004445
Type: single nucleotide variant
Location: chr7:142866026 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.36 · 1 PDB
Residue 391: the fibronectin type-iii 1 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-arg391his (accessed [today's date]).

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