PRR4

Chr 12

proline rich 4

Also known as: LPRP, PROL4

NCBI Gene: 11272 ENSG00000111215 UniProt: Q96NY8

The PRR4 protein is involved in cell adhesion through interactions with other proteins including NECTIN1. Mutations in this gene cause autosomal recessive lacrimo-auriculo-dento-digital syndrome, which affects the lacrimal system, ears, teeth, and digits. This gene is not highly constrained against loss-of-function variants.

Summary from RefSeq, UniProt

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Primary Disease Associations & Inheritance

UniProtEctodermal dysplasia-syndactyly syndrome 1

Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

1.72

LOEUF

Mechanism· predicted

Clinical Summary— PRR4

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

40 unique Pathogenic / Likely Pathogenic· 20 VUS of 65 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.72LOEUF

pLI 0.044

Z-score 0.56

OE 0.66 (0.26–1.72)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-0.14Z-score

OE missense 1.05 (0.87–1.27)

75 obs / 71.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.66 (0.26–1.72)

0≤0.351.4

Missense OE1.05 (0.87–1.27)

0≤0.61.4

Synonymous OE1.12

0≤1.21.6

LoF obs/exp: 2 / 3.0Missense obs/exp: 75 / 71.6Syn Z: -0.48

0.91top 5%

GOF

0.4776th %ile

LOF

0.1399th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

65 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38

Likely Pathogenic2

VUS20

Likely Benign3

Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	38	38
Likely Pathogenic	0	2	2
VUS	18	2	20
Likely Benign	2	1	3
Benign	2	0	2
Total	22	43	65

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

View in ClinVar →

Protein Context — Lollipop Plot

PRR4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

TNBC - Triple-Negative Breast CancerHR+ Breast Cancer

SC-101 in Subjects With Advanced NECTIN4-Amplified Cancers

NOT YET RECRUITING

NCT07080619Phase PHASE2Tianjin ConjuStar Biologics Co., Ltd.Started 2025-09-20

SC-101

Bladder (Urothelial, Transitional Cell) Cancer Metastatic or UnresectableUpper Tract Urothelial Cancer

DDR Genes Alteration and Response to Platinum-based Chemotherapy in Advanced Urothelial Cancer.

RECRUITING

NCT06820255Phase PHASE4Fondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-01-07

Platinum + GemcitabineAvelumab first-line maintenanceNGS test for DDR alterations

Advanced Malignant Solid NeoplasmMetastatic Malignant Solid Neoplasm

Personalized Antibody-Drug Conjugate Therapy Based on RNA and Protein Testing for the Treatment of Advanced or Metastatic Solid Tumors (The ADC MATCH Screening and Treatment Trial)

RECRUITING

NCT06311214Phase PHASE2National Cancer Institute (NCI)Started 2025-03-18

Biopsy ProcedureBiospecimen CollectionComputed Tomography

Locally Advanced Bladder Urothelial CarcinomaLocally Advanced Renal Pelvis Urothelial CarcinomaLocally Advanced Ureter Urothelial Carcinoma

Testing Combination Erdafitinib and Enfortumab Vedotin in Metastatic Bladder Cancer After Treatment With Chemotherapy and Immunotherapy

ACTIVE NOT RECRUITING

NCT04963153Phase PHASE1National Cancer Institute (NCI)Started 2022-07-07

Biospecimen CollectionBone ScanComputed Tomography

Clinical Literature

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Landmark / reviewRecent case evidence

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