# NM_153240.5(NPHP3):c.406del (p.Thr136fs)

https://sugi.bio/variant/nphp3-p-thr136fs

## Summary

**NPHP3 p.Thr136fs (c.406del)** is classified **Pathogenic/Likely pathogenic** in NPHP3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-15). Ultra-rare (popmax 0.0115%, nfe); Associated with NPHP3-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1379989124 · 7 submitters · 4 linked conditions · ultra-rare (popmax 0.0115%, nfe)

## 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 NPHP3-related disorder.

*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:** [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.Thr136fs |
| Coding change (HGVS c.) | c.406del |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| dbSNP | [rs1379989124](https://www.ncbi.nlm.nih.gov/snp/rs1379989124/) |
| Variant type | Deletion |
| Location | chr3:132719818-132719818 (GRCh38) |
| ClinVar | [VCV598394](https://www.ncbi.nlm.nih.gov/clinvar/variation/598394/) |

**All HGVS expressions:** `NC_000003.11:g.132438667del`, `NC_000003.12:g.132719823del`, `NG_008130.2:g.7615del`, `NM_153240.5:c.406del`, `NR_037804.1:n.510del`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 9.904, GERP 1.54, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.873, pLI 1.4471e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 27**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0115%** (nfe) · FAF95 0.0099% · FAF99 0.0093% · 134/1,164,622 in the highest group · 138/1,588,106 alleles overall — ultra-rare (popmax 0.0115%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0115% | 8,691 |
| South Asian | 0.00229% | 43,704 |
| Admixed American | 0.0017% | 58,968 |
| African / African-American | 0.00134% | 74,408 |

*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 2025-12-15.

**Submitter consensus:** conflicting (6 Pathogenic, 1 Likely pathogenic).

**Submission history:** 7 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2018-08-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-15 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-06-24 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-19 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-23 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-09-03 |
| MVZ Medizinische Genetik Mainz | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-05 |

## Associated conditions {#conditions}

[NPHP3-related disorder](https://sugi.bio/atlas/disease/nphp3-related-disorder/), [nephronophthisis 3](https://sugi.bio/atlas/disease/nephronophthisis-3/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/), [congenital anomaly of kidney and urinary tract](https://sugi.bio/atlas/disease/congenital-anomaly-of-kidney-and-urinary-tract/).

**Reported phenotype names (ClinVar):** NPHP3-related disorder, not provided, Nephronophthisis, Congenital anomaly of kidney and urinary tract, Nephronophthisis 3, NPHP3-related disorders, NPHP3-related condition, none provided, Juvenile Nephronophthisis, Adolescent nephronophthisis.

## Similar variants {#similar}

Related NPHP3 variant pages (same residue, condition, or type): [NPHP3 p.Thr136=](/variant/nphp3-p-thr136), [NPHP3 c.3570+1del](/variant/nphp3-c-3570-plus-1del), [NPHP3 p.Arg157fs](/variant/nphp3-p-arg157fs), [NPHP3 p.Glu90_Tyr91insTer](/variant/nphp3-p-glu90-tyr91inster), [NPHP3 p.His559fs](/variant/nphp3-p-his559fs), [NPHP3 p.Met491fs](/variant/nphp3-p-met491fs), [NPHP3 p.Phe1001fs](/variant/nphp3-p-phe1001fs), [NPHP3 p.Val363fs](/variant/nphp3-p-val363fs).

### 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 598394). 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.*