Is EPHB6 p.Val738Met (c.2212G>A) pathogenic?

EPHB6 p.Val738Met (c.2212G>A) is classified Uncertain significance in EPHB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). Ultra-rare (popmax 0.0205%, nfe).

How common is EPHB6 p.Val738Met (c.2212G>A) in the general population?

EPHB6 p.Val738Met (c.2212G>A) is ultra-rare (popmax 0.0205%, nfe) (gnomAD).

EPHB6 p.Val738Met

c.2212G>A · rs367947692 · VCV2213269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0205%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.851	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0205% European (non-Finnish) · 242/1,180,036 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0175%

Overall 0.0174% 280/1,613,796 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0448%	2,232
European (non-Finnish)grpmax	0.0205%	4,876
African / African-American	0.0107%	9,366
Admixed American	0.00333%	30,002

Remaining individuals 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.Val738Met
Coding: c.2212G>A
MANE Select: NM_004445
dbSNP: rs367947692
Type: single nucleotide variant
Location: chr7:142868665 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.36 · 1 PDB
Residue 738: 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-val738met (accessed [today's date]).

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