Is CDHR1 p.Phe246= (c.738C>T) pathogenic?

CDHR1 p.Phe246= (c.738C>T) is classified Likely benign in CDHR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-08). Ultra-rare (popmax 0.0725%, sas).

How common is CDHR1 p.Phe246= (c.738C>T) in the general population?

CDHR1 p.Phe246= (c.738C>T) is ultra-rare (popmax 0.0725%, sas) (gnomAD).

CDHR1 p.Phe246=

c.738C>T · rs141693979 · VCV1082318

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0725%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.4	GERP -0.77
Overall
CADD	11.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0725% South Asian · 66/91,088 alleles

Filtering AF 0.0584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00768% 124/1,614,232 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.128%	779
South Asiangrpmax	0.0725%	1,380
Remaining individualsnot grpmax-eligible	0.0096%	10,419
African / African-American	0.00533%	18,766
European (non-Finnish)	0.000847%	118,004

Ashkenazi Jewish 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: CDHR1
Protein: p.Phe246=
Coding: c.738C>T
MANE Select: NM_033100
dbSNP: rs141693979
Type: single nucleotide variant
Location: chr10:84203078 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.79
Residue 246: the cadherin 2 domain

Full CDHR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR1 c.1168-1G>C Pathogenic/Likely pathogenic ★★ same type
CDHR1 c.1321-1G>A Likely pathogenic ★★ same type
CDHR1 c.1485+2T>C Pathogenic ★★ same type
CDHR1 c.1485+2T>G Pathogenic ★★ same type
CDHR1 c.1554-2A>C Pathogenic/Likely pathogenic ★★ same type
CDHR1 c.297+1G>T Pathogenic ★★ same type
CDHR1 c.525+1G>A Pathogenic ★★ same type
CDHR1 c.526-1G>A Likely pathogenic ★★ 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/cdhr1-p-phe246 (accessed [today's date]).

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