# NM_015102.5(NPHP4):c.1421_1423delinsCGTGG (p.Lys474fs)

https://sugi.bio/variant/nphp4-p-lys474fs

## Summary

**NPHP4 p.Lys474fs (c.1421_1423delinsCGTGG)** is classified **Pathogenic/Likely pathogenic** in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-04). No gnomAD frequency available for this variant; Associated with Senior-Loken syndrome 4.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1553178047 · 3 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the NPHP4 gene that is considered likely disease-causing, submitted by 3 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.Lys474fs |
| Coding change (HGVS c.) | c.1421_1423delinsCGTGG |
| MANE Select transcript | [NM_015102](https://www.ncbi.nlm.nih.gov/nuccore/NM_015102) |
| dbSNP | [rs1553178047](https://www.ncbi.nlm.nih.gov/snp/rs1553178047/) |
| Variant type | Indel |
| Location | chr1:5927667-5927669 (GRCh38) |
| ClinVar | [VCV503803](https://www.ncbi.nlm.nih.gov/clinvar/variation/503803/) |

**All HGVS expressions:** `NC_000001.10:g.5987727_5987729delinsCCACG`, `NC_000001.11:g.5927667_5927669delinsCCACG`, `NG_011724.2:g.69803_69805delinsCGTGG`, `NM_001291593.2:c.55_57delinsCGTGG`, `NM_001291594.2:c.55_57delinsCGTGG`, `NM_015102.3:c.1421_1423delAACinsCGTGG`, `NM_015102.5:c.1421_1423delinsCGTGG`, `NR_111987.2:n.1641_1643delinsCGTGG`

## 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 2.822, GERP -0.284, phastCons 1 — highly conserved position (PP3-type support)
- 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 11 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 indel 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}

**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}

Residue **474** lies in the 'disordered' region.

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 2024-02-04.

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

**Submission history:** 3 submissions (2020–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-01-27 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-22 |

## 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/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Senior-Loken syndrome 4, not provided, Nephronophthisis 4, Nephronophthisis, NEPHRONOPHTHISIS 4, JUVENILE, none provided, Juvenile Nephronophthisis.

## Similar variants {#similar}

Related NPHP4 variant pages (same residue, condition, or type): [NPHP4 p.Gln748Lys](/variant/nphp4-p-gln748lys), [NPHP4 p.Leu1164fs](/variant/nphp4-p-leu1164fs), [NPHP4 p.Gly929Arg](/variant/nphp4-p-gly929arg), [NPHP4 p.Met1075Trp](/variant/nphp4-p-met1075trp), [NPHP4 p.Val291_Phe297delinsLeu](/variant/nphp4-p-val291-phe297delinsleu), [NPHP4 c.2304+1G>A](/variant/nphp4-c-2304-plus-1g-a), [NPHP4 c.2611+1G>A](/variant/nphp4-c-2611-plus-1g-a), [NPHP4 c.2611+1G>C](/variant/nphp4-c-2611-plus-1g-c).

### 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 503803). 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.*