# NM_015102.5(NPHP4):c.2802C>T (p.Arg934=)

https://sugi.bio/variant/nphp4-p-arg934

## Summary

**NPHP4 p.Arg934= (c.2802C>T)** is classified **Benign** in NPHP4 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). Common (popmax 74.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Senior-Loken syndrome 4.

**At a glance:** Benign · review: Multiple submitters · rsID rs3747992 · 12 submitters · 3 linked conditions · common (popmax 74.7%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the NPHP4 gene that is classified as benign — not considered disease-causing, submitted by 12 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.Arg934= |
| Coding change (HGVS c.) | c.2802C>T |
| MANE Select transcript | [NM_015102](https://www.ncbi.nlm.nih.gov/nuccore/NM_015102) |
| dbSNP | [rs3747992](https://www.ncbi.nlm.nih.gov/snp/rs3747992/) |
| Variant type | single nucleotide variant |
| Location | chr1:5877108-5877108 (GRCh38) |
| ClinVar | [VCV95679](https://www.ncbi.nlm.nih.gov/clinvar/variation/95679/) |

**All HGVS expressions:** `NC_000001.10:g.5937168G>A`, `NC_000001.11:g.5877108G>A`, `NG_011724.2:g.120364C>T`, `NM_001291593.2:c.1263C>T`, `NM_001291594.2:c.1266C>T`, `NM_015102.5:c.2802C>T`, `NR_111987.2:n.3306C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 74.7%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 -1.124, GERP -3.28 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.134**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.26 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **74.7%** (eas) · FAF95 74% · FAF99 73.7% · 32,647/43,708 in the highest group · 629,577/1,575,438 alleles overall — common (popmax 74.7%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 74.7% | 1 |
| Admixed American | 48.8% | 2 |
| South Asian | 41.6% | 2 |
| Remaining individuals (not grpmax-eligible) | 40.2% | 2 |
| Finnish (not grpmax-eligible) | 39% | 3 |
| European (non-Finnish) | 39% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 37.4% | 3 |
| Middle Eastern | 34.4% | 3 |
| Amish (not grpmax-eligible) | 31.7% | 3 |
| African / African-American | 27.9% | 4 |

*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 **934** lies in the 'sufficient for basal bodies localization' region; 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** unanimous (13/13 Benign).

**Submission history:** 13 submissions (2013–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-03-24 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing | 2016-01-27 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-09-05 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-05-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2013-10-04 |

## 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 specified, Nephronophthisis, Nephronophthisis 4, not provided, AllHighlyPenetrant, NEPHRONOPHTHISIS 4, JUVENILE, none provided, Juvenile Nephronophthisis.

## Same-residue context {#hotspot}

Residue **934** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NPHP4 p.Arg934fs](/variant/nphp4-p-arg934fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NPHP4 variant pages (same residue, condition, or type): [NPHP4 p.Arg934Cys](/variant/nphp4-p-arg934cys), [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), [NPHP4 c.3644+1G>A](/variant/nphp4-c-3644-plus-1g-a), [NPHP4 c.3644+1G>T](/variant/nphp4-c-3644-plus-1g-t), [NPHP4 c.517+1G>A](/variant/nphp4-c-517-plus-1g-a), [NPHP4 c.518-2A>G](/variant/nphp4-c-518-minus-2a-g).

### 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 95679). 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.*