# NM_001128178.3(NPHP1):c.385_386del (p.Ser129fs)

https://sugi.bio/variant/nphp1-p-ser129fs

## Summary

**NPHP1 p.Ser129fs (c.385_386del)** is classified **Pathogenic/Likely pathogenic** in NPHP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). Very rare (popmax 0.00134%, afr); Associated with nephronophthisis.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs757139057 · 3 submitters · 4 linked conditions · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the NPHP1 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to nephronophthisis.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NPHP1 is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Nephronophthisis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Abnormality of retinal pigmentation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000206/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.Ser129fs |
| Coding change (HGVS c.) | c.385_386del |
| MANE Select transcript | [NM_001128178](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128178) |
| dbSNP | [rs757139057](https://www.ncbi.nlm.nih.gov/snp/rs757139057/) |
| Variant type | Deletion |
| Location | chr2:110169942-110169943 (GRCh38) |
| ClinVar | [VCV3239952](https://www.ncbi.nlm.nih.gov/clinvar/variation/3239952/) |

**All HGVS expressions:** `NC_000002.11:g.110927519_110927520del`, `NC_000002.12:g.110169942_110169943del`, `NG_008287.1:g.40120_40121del`, `NM_000272.4:c.385_386del`, `NM_000272.5:c.385_386del`, `NM_001128178.3:c.385_386del`, `NM_001128179.3:c.199_200del`, `NM_001374256.1:c.385_386del`, `NM_001374257.1:c.385_386del`, `NM_207181.4:c.385_386del`

## 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 -0.123, GERP -2.72 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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.
- CADD: **PHRED 23.3**. 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.
- Repeat context: **simple_repeat** ((TTCCTC)n). The alignment of this deletion 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 (gnomAD v4.1): grpmax **0.00134%** (afr) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/74,590 in the highest group · 4/1,603,088 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00134% | 74,590 |
| European (non-Finnish) | 0.000256% | 390,174 |

*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 **129** lies in the 'disordered' region.

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-21.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-29 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-21 |

## Associated conditions {#conditions}

[nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/), [nephronophthisis 1](https://sugi.bio/atlas/disease/nephronophthisis-1/), [Senior-Loken syndrome 1](https://sugi.bio/atlas/disease/senior-loken-syndrome-1/), [Joubert syndrome with renal defect](https://sugi.bio/atlas/disease/joubert-syndrome-with-renal-defect/).

**Reported phenotype names (ClinVar):** Nephronophthisis, Joubert syndrome with renal defect, Nephronophthisis 1, Senior-Loken syndrome 1, Juvenile Nephronophthisis, Nephronophthisis familial juvenile, JUVENILE NEPHRONOPHTHISIS WITH LEBER AMAUROSIS, JOUBERT SYNDROME 4.

## Similar variants {#similar}

Related NPHP1 variant pages (same residue, condition, or type): [NPHP1 p.Ser129del](/variant/nphp1-p-ser129del), [NPHP1 p.Ser129Thr](/variant/nphp1-p-ser129thr), [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.Glu454fs](/variant/nphp1-p-glu454fs), [NPHP1 p.Ile517fs](/variant/nphp1-p-ile517fs), [NPHP1 p.Lys185fs](/variant/nphp1-p-lys185fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3239952). 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.*