Is CDHR1 p.Pro278Leu (c.833C>T) pathogenic?

CDHR1 p.Pro278Leu (c.833C>T) is classified Conflicting classifications of pathogenicity in CDHR1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.1947); Rare (popmax 0.169%, sas).

How common is CDHR1 p.Pro278Leu (c.833C>T) in the general population?

CDHR1 p.Pro278Leu (c.833C>T) is rare (popmax 0.169%, sas) (gnomAD).

What do computational predictors say about CDHR1 p.Pro278Leu (c.833C>T)?

AlphaMissense predicts likely benign (score 0.1947) — an in-silico prediction, not a clinical call.

CDHR1 p.Pro278Leu

c.833C>T · rs543254581 · VCV290839

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1947 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.169%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1947	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -10.46	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 4.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.035 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.169% South Asian · 154/91,064 alleles

Filtering AF 0.147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.139%

Overall 0.0108% 174/1,613,674 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.169%	591
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00267%	37,502
European (non-Finnish)	0.00127%	78,642

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.Pro278Leu
Coding: c.833C>T
MANE Select: NM_033100
dbSNP: rs543254581
Type: single nucleotide variant
Location: chr10:84204576 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.79
Residue 278: the cadherin 3 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-pro278leu (accessed [today's date]).

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