# NM_153240.5(NPHP3):c.2369T>C (p.Leu790Pro)

https://sugi.bio/variant/nphp3-p-leu790pro

## Summary

**NPHP3 p.Leu790Pro (c.2369T>C)** is classified **Pathogenic/Likely pathogenic** in NPHP3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.9148); Ultra-rare (popmax 0.0111%, eas); Associated with renal-hepatic-pancreatic dysplasia 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs398124546 · 7 submitters · 5 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0111%, eas)

## For patients & families {#patients}

This is a change in the NPHP3 gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to renal-hepatic-pancreatic dysplasia 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018431/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPHP3](https://sugi.bio/atlas/gene/NPHP3/) |
| Protein change (HGVS p.) | p.Leu790Pro |
| Coding change (HGVS c.) | c.2369T>C |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| dbSNP | [rs398124546](https://www.ncbi.nlm.nih.gov/snp/rs398124546/) |
| Variant type | single nucleotide variant |
| Location | chr3:132692760-132692760 (GRCh38) |
| ClinVar | [VCV96511](https://www.ncbi.nlm.nih.gov/clinvar/variation/96511/) |

**All HGVS expressions:** `NC_000003.11:g.132411604A>G`, `NC_000003.12:g.132692760A>G`, `NG_008130.2:g.34673T>C`, `NM_153240.5:c.2369T>C`, `NR_037804.1:n.2375T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9148) — concordant with the pathogenic call
- REVEL 0.863 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.924 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.219, GERP 1.59, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in NPHP3 (of 7,784 modeled).
- CADD: **PHRED 27.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (132,681,913–132,692,805), spanning 10,892 bp. Chi-square p 0.0019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0111%** (eas) · FAF95 0.00435% · FAF99 0.00276% · 5/44,850 in the highest group · 5/1,614,024 alleles overall — ultra-rare (popmax 0.0111%, eas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**NPHP3** population constraint: LOEUF 0.873, pLI 1.4471e-21, missense-Z 0.91316. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **nephronophthisis** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.59, 9% of residues very-high.

**1 experimental structure(s)** (PDB): [5L7K](https://www.rcsb.org/structure/5L7K).

## What this gene does {#gene-function}

*Describes the biological roles of NPHP3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

NPHP3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Trafficking of myristoylated proteins to the cilium](https://reactome.org/content/detail/R-HSA-5624138) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** kidney development, heart looping, atrial septum development, determination of left/right symmetry, lung development, determination of pancreatic left/right asymmetry.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-20.

**Submitter consensus:** conflicting (5 Likely pathogenic, 2 Pathogenic).

**Submission history:** 7 submissions (2016–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-17 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-08-08 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-05-08 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-09 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Eurofins Ntd Llc (ga) | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-07-20 |

## Associated conditions {#conditions}

[renal-hepatic-pancreatic dysplasia 1](https://sugi.bio/atlas/disease/renal-hepatic-pancreatic-dysplasia-1/), [NPHP3-related Meckel-like syndrome](https://sugi.bio/atlas/disease/nphp3-related-meckel-like-syndrome/), [nephronophthisis 3](https://sugi.bio/atlas/disease/nephronophthisis-3/), [Joubert syndrome and related disorders](https://sugi.bio/atlas/disease/joubert-syndrome-and-related-disorders/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Renal-hepatic-pancreatic dysplasia 1, not provided, Joubert syndrome and related disorders, Nephronophthisis, NPHP3-related disorder, Nephronophthisis 3, NPHP3-related Meckel-like syndrome, NPHP3-related condition, NPHP3-related disorders, Adolescent nephronophthisis.

## Similar variants {#similar}

Related NPHP3 variant pages (same residue, condition, or type): [NPHP3 c.1985+1G>A](/variant/nphp3-c-1985-plus-1g-a), [NPHP3 c.3201+1G>T](/variant/nphp3-c-3201-plus-1g-t), [NPHP3 c.393+1G>C](/variant/nphp3-c-393-plus-1g-c), [NPHP3 c.520-1G>T](/variant/nphp3-c-520-minus-1g-t), [NPHP3 c.823+1G>T](/variant/nphp3-c-823-plus-1g-t), [NPHP3 c.958-2A>G](/variant/nphp3-c-958-minus-2a-g), [NPHP3 p.Arg1125Ter](/variant/nphp3-p-arg1125ter), [NPHP3 p.Arg1259Ter](/variant/nphp3-p-arg1259ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 96511). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*