# NM_015102.5(NPHP4):c.2611C>T (p.Arg871Ter)

https://sugi.bio/variant/nphp4-p-arg871ter

## Summary

**NPHP4 p.Arg871Ter (c.2611C>T)** is classified **Pathogenic/Likely pathogenic** in NPHP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-24). Very rare (popmax 0.000593%, nfe); Associated with NPHP4-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2100733826 · 2 submitters · 2 linked conditions · very rare (popmax 0.000593%, nfe)

## 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 NPHP4-related disorder.

*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.Arg871Ter |
| Coding change (HGVS c.) | c.2611C>T |
| MANE Select transcript | [NM_015102](https://www.ncbi.nlm.nih.gov/nuccore/NM_015102) |
| dbSNP | [rs2100733826](https://www.ncbi.nlm.nih.gov/snp/rs2100733826/) |
| Variant type | single nucleotide variant |
| Location | chr1:5880114-5880114 (GRCh38) |
| ClinVar | [VCV1455063](https://www.ncbi.nlm.nih.gov/clinvar/variation/1455063/) |

**All HGVS expressions:** `NC_000001.10:g.5940174G>A`, `NC_000001.11:g.5880114G>A`, `NG_011724.2:g.117358C>T`, `NM_001291593.2:c.1072C>T`, `NM_001291594.2:c.1075C>T`, `NM_015102.5:c.2611C>T`, `NR_111987.2:n.2828C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.92) — consistent with the pathogenic call
- Conservation: phyloP -1.015, GERP -3.41 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **nonsense (stop-gain)** — 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 19 of 30**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 38.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.13**, acceptor gain **0.00**, donor gain **0.92**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.92**.
- Pangolin: Δ**0.69** (gain), gain 0.69 / loss 0.24. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,710 in the highest group · 7/1,613,584 alleles overall — very rare (popmax 0.000593%, nfe).

*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 **871** 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-07-24.

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

**Submission history:** 2 submissions (2020–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-24 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-10-02 |

## Associated conditions {#conditions}

[NPHP4-related disorder](https://sugi.bio/atlas/disease/nphp4-related-disorder/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** NPHP4-related disorder, Nephronophthisis, NPHP4-related disorders, NPHP4-related condition, Juvenile Nephronophthisis.

## Similar variants {#similar}

Related NPHP4 variant pages (same residue, condition, or type): [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), [NPHP4 c.992+2T>C](/variant/nphp4-c-992-plus-2t-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 1455063). 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.*