# NM_001128178.3(NPHP1):c.361_362dup (p.Ser121fs)

https://sugi.bio/variant/nphp1-p-ser121fs

## Summary

**NPHP1 p.Ser121fs (c.361_362dup)** is classified **Likely pathogenic** in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). No gnomAD frequency available for this variant; Associated with nephronophthisis 1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2467405206 · 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 nephronophthisis 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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018645/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.Ser121fs |
| Coding change (HGVS c.) | c.361_362dup |
| MANE Select transcript | [NM_001128178](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128178) |
| dbSNP | [rs2467405206](https://www.ncbi.nlm.nih.gov/snp/rs2467405206/) |
| Variant type | Duplication |
| Location | chr2:110169965-110169966 (GRCh38) |
| ClinVar | [VCV2681747](https://www.ncbi.nlm.nih.gov/clinvar/variation/2681747/) |

**All HGVS expressions:** `NC_000002.11:g.110927543_110927544dup`, `NC_000002.12:g.110169966_110169967dup`, `NG_008287.1:g.40096_40097dup`, `NM_000272.5:c.361_362dup`, `NM_001128178.3:c.361_362dup`, `NM_001128179.3:c.175_176dup`, `NM_001374256.1:c.361_362dup`, `NM_001374257.1:c.361_362dup`, `NM_207181.4:c.361_362dup`

## 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 -4.003, GERP -2.93, phastCons 0.001 — 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 5 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 duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** ((TTCCTC)n). The alignment of this duplication is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- 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}

Residue **121** lies in the 'disordered' region; a modified residue (phosphoserine; by ck2).

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 2023-12-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Precision Medicine Center, Zhengzhou University | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-01 |

## Associated conditions {#conditions}

[nephronophthisis 1](https://sugi.bio/atlas/disease/nephronophthisis-1/).

**Reported phenotype names (ClinVar):** Nephronophthisis 1, Nephronophthisis familial juvenile.

## Similar variants {#similar}

Related NPHP1 variant pages (same residue, condition, or type): [NPHP1 p.Pro186fs](/variant/nphp1-p-pro186fs), [NPHP1 c.771+37_771+38dup](/variant/nphp1-c-771-plus-37-771-plus-38dup), [NPHP1 p.Gly161fs](/variant/nphp1-p-gly161fs), [NPHP1 p.Ile632fs](/variant/nphp1-p-ile632fs), [NPHP1 c.625-3dup](/variant/nphp1-c-625-minus-3dup), [NPHP1 c.143+1G>C](/variant/nphp1-c-143-plus-1g-c), [NPHP1 c.144-1G>A](/variant/nphp1-c-144-minus-1g-a), [NPHP1 c.1716+1G>T](/variant/nphp1-c-1716-plus-1g-t).

### 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 2681747). 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.*