# NM_015102.5(NPHP4):c.2031C>T (p.Pro677=)

https://sugi.bio/variant/nphp4-p-pro677

## Summary

**NPHP4 p.Pro677= (c.2031C>T)** is classified **Benign** in NPHP4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 3.45%, afr); Associated with nephronophthisis.

**At a glance:** Benign · review: Multiple submitters · rsID rs34373111 · 5 submitters · 3 linked conditions · low-frequency (popmax 3.45%, afr)

## For patients & families {#patients}

This is a change in the NPHP4 gene that is classified as benign — not considered disease-causing, submitted by 5 submitters, and is linked to nephronophthisis.

*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, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NPHP4 is a diagnostic-grade gene on 13 Genomics England panels |

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

- Renal insufficiency — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Abnormality of retinal pigmentation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000206/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.Pro677= |
| Coding change (HGVS c.) | c.2031C>T |
| MANE Select transcript | [NM_015102](https://www.ncbi.nlm.nih.gov/nuccore/NM_015102) |
| dbSNP | [rs34373111](https://www.ncbi.nlm.nih.gov/snp/rs34373111/) |
| Variant type | single nucleotide variant |
| Location | chr1:5904729-5904729 (GRCh38) |
| ClinVar | [VCV240966](https://www.ncbi.nlm.nih.gov/clinvar/variation/240966/) |

**All HGVS expressions:** `NC_000001.10:g.5964789G>A`, `NC_000001.11:g.5904729G>A`, `NG_011724.2:g.92743C>T`, `NM_001291593.2:c.492C>T`, `NM_001291594.2:c.495C>T`, `NM_015102.5:c.2031C>T`, `NR_111987.2:n.2248C>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 (below), not from a missing predictor score.
- Conservation: phyloP -5.362, GERP -3.28 — fast-evolving / accelerated position
- CADD: **PHRED 0.57**. 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>T, Δ0.43 acceptor gain), 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 **3.45%** (afr) · FAF95 3.34% · FAF99 3.3% · 2,592/75,038 in the highest group · 3,107/1,613,998 alleles overall — low-frequency (popmax 3.45%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.45% | 29 |
| Middle Eastern | 0.363% | 276 |
| Remaining individuals (not grpmax-eligible) | 0.344% | 291 |
| Admixed American | 0.257% | 390 |
| South Asian | 0.0176% | 5,693 |
| Finnish (not grpmax-eligible) | 0.0109% | 9,144 |
| European (non-Finnish) | 0.00831% | 12,040 |
| East Asian | 0.00446% | 22,442 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,602 |

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** unanimous (6/6 Benign).

**Submission history:** 6 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2021-06-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related NPHP4 variant pages (same residue, condition, or type): [NPHP4 p.Pro677Leu](/variant/nphp4-p-pro677leu), [NPHP4 p.Pro677Ser](/variant/nphp4-p-pro677ser), [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).

### 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 240966). 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.*