NPHP3

Chr 3AR

nephrocystin 3

Also known as: CFAP31, MKS7, NPH3, RHPD, RHPD1, SLSN3

NCBI Gene: 27031ENSG00000113971UniProt: Q7Z494

This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene. [provided by RefSeq, Feb 2011]

Primary Disease Associations & Inheritance

Nephronophthisis 3MIM #604387
AR
Meckel syndrome 7MIM #267010
AR
Nephronophthisis 3MIM #604387
AR
Renal-hepatic-pancreatic dysplasia 1MIM #208540
AR
695
ClinVar variants
94
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NPHP3
🧬
Gene-Disease Validity (ClinGen)
nephronophthisis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
94 Pathogenic / Likely Pathogenic· 321 VUS of 695 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.65LOEUF
pLI 0.000
Z-score 4.10
OE 0.50 (0.38–0.65)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.86Z-score
OE missense 0.91 (0.85–0.97)
627 obs / 690.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.50 (0.38–0.65)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.85–0.97)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 38 / 76.7Missense obs/exp: 627 / 690.9Syn Z: 1.41

ClinVar Variant Classifications

695 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic47
VUS321
Likely Benign217
Benign30
Conflicting33
47
Pathogenic
47
Likely Pathogenic
321
VUS
217
Likely Benign
30
Benign
33
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
0
31
0
47
Likely Pathogenic
32
2
13
0
47
VUS
4
281
29
7
321
Likely Benign
0
2
119
96
217
Benign
0
0
29
1
30
Conflicting
—33
Total52285221104695

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

View in ClinVar →

Protein Context — Lollipop Plot

NPHP3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NPHP3-related Senior-Loken syndrome

definitive
ARUndeterminedUncertain
Eye
G2P ↗

NPHP3-related nephronophthisis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Nephronophthisis 3

MIM #604387

Molecular basis of disorder known

Autosomal recessive
NEPHROCYSTIN 3; NPHP3
MIM #608002 · *

Meckel syndrome 7

MIM #267010

Molecular basis of disorder known

Autosomal recessive

Nephronophthisis 3

MIM #604387

Molecular basis of disorder known

Autosomal recessive

Renal-hepatic-pancreatic dysplasia 1

MIM #208540

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NPHP3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4.
Wang J et al.·Am J Ophthalmol
2023
Renal-hepatic-pancreatic dysplasia-1 with a novel NPHP3 genotype: a case report and review of the literature.
Zhu H et al.·BMC Pediatr
2022Review
NPHP3 splice acceptor site variant is associated with infantile nephronophthisis and asphyxiating thoracic dystrophy; A rare combination.
Ijaz A et al.·Eur J Med Genet
2022
A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families.
Olinger E et al.·Hum Mutat
2021
Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants.
Lord J et al.·Genet Med
2024
High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients.
Sun L et al.·Nephrology (Carlton)
2016Cohort
Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP.
Li J et al.·Pediatr Nephrol
2023
Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy.
Tang X et al.·J Med Genet
2022Cohort
Identification of a Splicing Variant c.3813-3A>G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis.
Zhang X et al.·Nephron
2023Case report
Mutations of NPHP2 and NPHP3 in infantile nephronophthisis.
Tory K et al.·Kidney Int
2009
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools