# NM_153240.5(NPHP3):c.*651del

https://sugi.bio/variant/nphp3-c-star-651del

## Summary

**NPHP3 c.*651del** is classified **Benign** in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-13). Common (popmax 41.8%, eas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs886058000 · 1 submitter · common (popmax 41.8%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the NPHP3 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter.

*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 | [NPHP3](https://sugi.bio/atlas/gene/NPHP3/) |
| Coding change (HGVS c.) | c.*651del |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| dbSNP | [rs886058000](https://www.ncbi.nlm.nih.gov/snp/rs886058000/) |
| Variant type | Deletion |
| Location | chr3:132681259-132681259 (GRCh38) |
| ClinVar | [VCV1259608](https://www.ncbi.nlm.nih.gov/clinvar/variation/1259608/) |

**All HGVS expressions:** `NC_000003.11:g.132400125del`, `NC_000003.12:g.132681281del`, `NG_008130.2:g.46174del`, `NM_153240.5:c.*651del`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 41.8%, 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 0.051, GERP -0.512, phastCons 0.044 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.497**. 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 deletion 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 **41.8%** (eas) · FAF95 39.8% · FAF99 39% · 1,140/2,728 in the highest group · 9,437/105,728 alleles overall — common (popmax 41.8%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 41.8% | 2 |
| South Asian | 14.7% | 7 |
| African / African-American | 11.6% | 9 |
| Middle Eastern | 10.1% | 10 |
| Amish (not grpmax-eligible) | 9.52% | 10 |
| Remaining individuals (not grpmax-eligible) | 9.16% | 11 |
| European (non-Finnish) | 6.48% | 15 |
| Admixed American | 6.47% | 15 |
| Ashkenazi Jewish (not grpmax-eligible) | 6.34% | 16 |
| Finnish (not grpmax-eligible) | 4.31% | 23 |

*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}

**NPHP3** population constraint: LOEUF 0.873, pLI 1.4471e-21, missense-Z 0.91316. *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** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.59, 9% of residues very-high.

**1 experimental structure(s)** (PDB): [5L7K](https://www.rcsb.org/structure/5L7K).

## What this gene does {#gene-function}

*Describes the biological roles of NPHP3 (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}

NPHP3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Trafficking of myristoylated proteins to the cilium](https://reactome.org/content/detail/R-HSA-5624138) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** kidney development, heart looping, atrial septum development, determination of left/right symmetry, lung development, determination of pancreatic left/right asymmetry.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-05-13.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-05-13 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related NPHP3 variant pages (same residue, condition, or type): [NPHP3 c.1888-7_1893del](/variant/nphp3-c-1888-minus-7-1893del), [NPHP3 c.3570+1del](/variant/nphp3-c-3570-plus-1del), [NPHP3 p.Arg157fs](/variant/nphp3-p-arg157fs), [NPHP3 p.Glu90_Tyr91insTer](/variant/nphp3-p-glu90-tyr91inster), [NPHP3 p.His559fs](/variant/nphp3-p-his559fs), [NPHP3 p.Met491fs](/variant/nphp3-p-met491fs), [NPHP3 p.Phe1001fs](/variant/nphp3-p-phe1001fs), [NPHP3 p.Thr136fs](/variant/nphp3-p-thr136fs).

### 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 1259608). 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.*