# NM_001128178.3(NPHP1):c.1064_1067del (p.Cys355fs)

https://sugi.bio/variant/nphp1-p-cys355fs

## Summary

**NPHP1 p.Cys355fs (c.1064_1067del)** is classified **Likely pathogenic** in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-02). No gnomAD frequency available for this variant; Associated with Joubert syndrome with renal defect.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2467332716 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the NPHP1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Joubert syndrome with renal defect.

*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/0010169/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPHP1](https://sugi.bio/atlas/gene/NPHP1/) |
| Protein change (HGVS p.) | p.Cys355fs |
| Coding change (HGVS c.) | c.1064_1067del |
| MANE Select transcript | [NM_001128178](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128178) |
| dbSNP | [rs2467332716](https://www.ncbi.nlm.nih.gov/snp/rs2467332716/) |
| Variant type | Deletion |
| Location | chr2:110160143-110160146 (GRCh38) |
| ClinVar | [VCV2677273](https://www.ncbi.nlm.nih.gov/clinvar/variation/2677273/) |

**All HGVS expressions:** `NC_000002.11:g.110917723_110917726del`, `NC_000002.12:g.110160146_110160149del`, `NG_008287.1:g.49917_49920del`, `NM_000272.5:c.1232_1235del`, `NM_001128178.3:c.1064_1067del`, `NM_001128179.3:c.875_878del`, `NM_001374256.1:c.1061_1064del`, `NM_001374257.1:c.1064_1067del`, `NM_207181.4:c.1229_1232del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -5.125, GERP -3.22 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.92, pLI 4.482e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 20**, so the transcript is predicted to undergo NMD.
- 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**NPHP1** population constraint: LOEUF 0.92, pLI 4.482e-10, missense-Z 0.65749. *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 1** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.22, 45% of residues very-high.

**2 experimental structure(s)** (PDB): [1S1N](https://www.rcsb.org/structure/1S1N), [6O1Q](https://www.rcsb.org/structure/6O1Q).

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

*Describes the biological roles of NPHP1 (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}

NPHP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |

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

**Biological process:** positive regulation of bicellular tight junction assembly.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-02.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-02-02 |

## Associated conditions {#conditions}

[Joubert syndrome with renal defect](https://sugi.bio/atlas/disease/joubert-syndrome-with-renal-defect/).

**Reported phenotype names (ClinVar):** Joubert syndrome with renal defect, JOUBERT SYNDROME 4.

## Similar variants {#similar}

Related NPHP1 variant pages (same residue, condition, or type): [NPHP1 c.141_143+40del](/variant/nphp1-c-141-143-plus-40del), [NPHP1 p.Asn61fs](/variant/nphp1-p-asn61fs), [NPHP1 p.Asp162fs](/variant/nphp1-p-asp162fs), [NPHP1 p.Ile517fs](/variant/nphp1-p-ile517fs), [NPHP1 p.Lys185fs](/variant/nphp1-p-lys185fs), [NPHP1 p.Lys377fs](/variant/nphp1-p-lys377fs), [NPHP1 p.Ser129fs](/variant/nphp1-p-ser129fs), [NPHP1 p.Ser29fs](/variant/nphp1-p-ser29fs).

### 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 2677273). 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.*