NPHP3

Chr 3AR

nephrocystin 3

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

NCBI Gene: 27031 ENSG00000113971 UniProt: Q7Z494 OMIM: 604387

The protein is required for normal ciliary development and function, regulates Wnt signaling pathways, and is essential for renal tubular development and convergent extension cell movements. Mutations cause autosomal recessive ciliopathies including nephronophthisis type 3 (progressive kidney disease), Meckel syndrome type 7 (severe developmental disorder), and renal-hepatic-pancreatic dysplasia affecting multiple organ systems. The gene is highly constrained against loss-of-function variants (LOEUF 0.649), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.654 OMIM phenotypes

Clinical Summary— NPHP3

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Gene-Disease Validity (ClinGen)

nephronophthisis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

168 unique Pathogenic / Likely Pathogenic· 682 VUS of 1444 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NPHP3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.000

Z-score 4.10

OE 0.50 (0.38–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.86Z-score

OE missense 0.91 (0.85–0.97)

627 obs / 690.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.38–0.65)

0≤0.351.4

Missense OE?0.91 (0.85–0.97)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 38 / 76.7Missense obs/exp: 627 / 690.9Syn Z: 1.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNPHP3-related Senior-Loken syndromeOTHERAR

definitiveNPHP3-related nephronophthisisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6161th %ile

GOF

0.6247th %ile

LOF

0.3356th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

1444 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic91

Likely Pathogenic77

VUS682

Likely Benign424

Benign61

Conflicting105

Pathogenic

Likely Pathogenic

682

VUS

424

Likely Benign

Benign

105

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	82	2	7	0	91
Likely Pathogenic	66	8	2	1	77
VUS	6	597	68	11	682
Likely Benign	0	7	214	203	424
Benign	0	0	58	3	61
Conflicting	—				105
Total	154	614	349	218	1,440

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap NPHP3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →