Is CDHR1 p.Arg280Ter (c.838C>T) pathogenic?

CDHR1 p.Arg280Ter (c.838C>T) is classified Pathogenic in CDHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). Ultra-rare (popmax 0.0164%, mid).

How common is CDHR1 p.Arg280Ter (c.838C>T) in the general population?

CDHR1 p.Arg280Ter (c.838C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

CDHR1 p.Arg280Ter

c.838C>T · rs191858417 · VCV844427

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 17
Splicing
SpliceAI	Δ0.23	donor loss · deltas
Pangolin	Δ0.44	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP 3.8, phastCons 0.97
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00124% 20/1,613,260 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0016%	62,460
Finnishnot grpmax-eligible	0.00156%	64,034
African / African-American	0.00134%	74,886
European (non-Finnish)	0.0011%	90,719

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.Arg280Ter
Coding: c.838C>T
MANE Select: NM_033100
dbSNP: rs191858417
Type: single nucleotide variant
Location: chr10:84204581 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.79
Residue 280: the cadherin 3 domain

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

Similar variants

CDHR1 p.Arg280Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CDHR1 p.Arg280= Likely benign ★ same residue
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

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-arg280ter (accessed [today's date]).

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