# NM_015102.5(NPHP4):c.1788_1791del (p.Ser597fs)

https://sugi.bio/variant/nphp4-p-ser597fs

## Summary

**NPHP4 p.Ser597fs (c.1788_1791del)** is classified **Pathogenic/Likely pathogenic** in NPHP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-23). Ultra-rare (popmax 0.0224%, eas); Associated with Senior-Loken syndrome 4.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs747699128 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.0224%, eas)

## For patients & families {#patients}

This is a change in the NPHP4 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Senior-Loken syndrome 4.

*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, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Diagnostic panels | NPHP4 is a diagnostic-grade gene on 13 Genomics England panels |

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

- Visual impairment — Very frequent (99-80%)
- Retinal dystrophy — Very frequent (99-80%)
- Hypertension — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Stage 5 chronic kidney disease — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Chronic kidney disease — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015406/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPHP4](https://sugi.bio/atlas/gene/NPHP4/) |
| Protein change (HGVS p.) | p.Ser597fs |
| Coding change (HGVS c.) | c.1788_1791del |
| MANE Select transcript | [NM_015102](https://www.ncbi.nlm.nih.gov/nuccore/NM_015102) |
| dbSNP | [rs747699128](https://www.ncbi.nlm.nih.gov/snp/rs747699128/) |
| Variant type | Deletion |
| Location | chr1:5905456-5905459 (GRCh38) |
| ClinVar | [VCV225422](https://www.ncbi.nlm.nih.gov/clinvar/variation/225422/) |

**All HGVS expressions:** `NC_000001.10:g.5965517_5965520del`, `NC_000001.11:g.5905457_5905460del`, `NG_011724.2:g.92013_92016del`, `NM_001291593.2:c.249_252del`, `NM_001291594.2:c.252_255del`, `NM_015102.5:c.1788_1791del`, `NR_111987.2:n.2005_2008del`

## 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 -0.561, GERP -4.26 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.183, pLI 1.9288e-50. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 15 of 30**, 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 (gnomAD v4.1): grpmax **0.0224%** (eas) · FAF95 0.0121% · FAF99 0.0092% · 10/44,700 in the highest group · 10/1,607,642 alleles overall — ultra-rare (popmax 0.0224%, 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}

**NPHP4** population constraint: LOEUF 1.183, pLI 1.9288e-50, missense-Z -0.325. *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 4** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 72.44, 17% of residues very-high.

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

*Describes the biological roles of NPHP4 (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}

NPHP4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Signaling by Hippo](https://reactome.org/content/detail/R-HSA-2028269) | curated |

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

**Biological process:** negative regulation of canonical Wnt signaling pathway, 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 2025-09-23.

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

**Submission history:** 2 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Likely pathogenic | criteria provided, single submitter | reference population | 2016-03-18 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-23 |

## Associated conditions {#conditions}

[Senior-Loken syndrome 4](https://sugi.bio/atlas/disease/senior-loken-syndrome-4/), [nephronophthisis 4](https://sugi.bio/atlas/disease/nephronophthisis-4/).

**Reported phenotype names (ClinVar):** Senior-Loken syndrome 4, Nephronophthisis 4, NEPHRONOPHTHISIS 4, JUVENILE.

## Similar variants {#similar}

Related NPHP4 variant pages (same residue, condition, or type): [NPHP4 c.3817-12_3818del](/variant/nphp4-c-3817-minus-12-3818del), [NPHP4 p.Ala279fs](/variant/nphp4-p-ala279fs), [NPHP4 p.Ala565fs](/variant/nphp4-p-ala565fs), [NPHP4 p.Gln1050fs](/variant/nphp4-p-gln1050fs), [NPHP4 p.Gly1028fs](/variant/nphp4-p-gly1028fs), [NPHP4 p.Gly529fs](/variant/nphp4-p-gly529fs), [NPHP4 p.Lys424fs](/variant/nphp4-p-lys424fs), [NPHP4 p.Phe63fs](/variant/nphp4-p-phe63fs).

### 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 225422). 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.*