# NM_015102.5(NPHP4):c.3272dup (p.Ser1092fs)

https://sugi.bio/variant/nphp4-p-ser1092fs

## Summary

**NPHP4 p.Ser1092fs (c.3272dup)** is classified **Pathogenic** in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-09). Ultra-rare (popmax 0.0176%, sas); Associated with Cystic renal disease.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs777884325 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0176%, sas)

## For patients & families {#patients}

This is a change in the NPHP4 gene that is considered disease-causing, submitted by 3 submitters, and is linked to Cystic renal disease.

*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:** [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.Ser1092fs |
| Coding change (HGVS c.) | c.3272dup |
| MANE Select transcript | [NM_015102](https://www.ncbi.nlm.nih.gov/nuccore/NM_015102) |
| dbSNP | [rs777884325](https://www.ncbi.nlm.nih.gov/snp/rs777884325/) |
| Variant type | Duplication |
| Location | chr1:5873294-5873295 (GRCh38) |
| ClinVar | [VCV2202693](https://www.ncbi.nlm.nih.gov/clinvar/variation/2202693/) |

**All HGVS expressions:** `NC_000001.10:g.5933355dup`, `NC_000001.11:g.5873295dup`, `NG_011724.2:g.124177dup`, `NM_001291593.2:c.1733dup`, `NM_001291594.2:c.1736dup`, `NM_015102.3:c.3272dup`, `NM_015102.5:c.3272dup`, `NR_111987.2:n.4039dup`

## 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 -7.84, GERP -3.4 — fast-evolving / accelerated position
- 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 23 of 30**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 18.71**. 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 duplication 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 **0.0176%** (sas) · FAF95 0.011% · FAF99 0.00888% · 16/91,086 in the highest group · 17/1,613,868 alleles overall — ultra-rare (popmax 0.0176%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0176% | 5,693 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,460 |

*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 **1092** lies in the 'sufficient for basal bodies localization' 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** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-09.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2023–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-02 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-09 |

## Associated conditions {#conditions}

[Cystic renal disease](https://sugi.bio/atlas/disease/cystic-renal-disease/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Cystic renal disease, Nephronophthisis, not provided, none provided, Juvenile Nephronophthisis.

## Similar variants {#similar}

Related NPHP4 variant pages (same residue, condition, or type): [NPHP4 p.Ser1092Pro](/variant/nphp4-p-ser1092pro), [NPHP4 p.His982fs](/variant/nphp4-p-his982fs), [NPHP4 p.Leu970fs](/variant/nphp4-p-leu970fs), [NPHP4 p.Ser251fs](/variant/nphp4-p-ser251fs), [NPHP4 p.Thr1004fs](/variant/nphp4-p-thr1004fs), [NPHP4 c.1306_1314dup](/variant/nphp4-c-1306-1314dup), [NPHP4 c.3231+7dup](/variant/nphp4-c-3231-plus-7dup), [NPHP4 p.Ala1029fs](/variant/nphp4-p-ala1029fs).

### 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 2202693). 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.*