CDHR2

Chr 5

cadherin related family member 2

Also known as: PCDH24, PCLCK, PCLKC

NCBI Gene: 54825 ENSG00000074276 UniProt: Q9BYE9 OMIM: 619713

CDHR2 encodes a protocadherin that functions as a calcium-dependent cell adhesion molecule, forming complexes with CDHR5 to control microvillus packing and brush border formation in epithelial cells. Mutations cause autosomal recessive cone-rod dystrophy and retinal dystrophy, affecting photoreceptor function and leading to progressive vision loss. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the protocadherin family, which represents a subset of the larger cadherin superfamily. The members of the protocadherin family encode non-classical cadherins that function as calcium-dependent cell-cell adhesion molecules. This protocadherin represents a new candidate for tumor suppression. Alternatively spliced transcript variants that encode the same protein have been identified. [provided by RefSeq, Jan 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.85

Clinical Summary— CDHR2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

227 VUS of 277 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.000

Z-score 2.53

OE 0.65 (0.51–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.37Z-score

OE missense 0.96 (0.91–1.02)

767 obs / 796.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.51–0.85)

0≤0.351.4

Missense OE?0.96 (0.91–1.02)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 41 / 62.6Missense obs/exp: 767 / 796.5Syn Z: -0.91

This gene — mechanism propensity

0.76top 25%

GOF

0.78top 25%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

277 submitted variants in ClinVar

ClinVar

Classification Summary

VUS227

Likely Benign25

227

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	227	0	227
Likely Benign	17	8	25
Benign	0	0	0
Total	244	8	252

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

52 pathogenic / likely-pathogenic (of 59) ClinVar copy-number / structural variants overlap CDHR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →