# NM_153240.5(NPHP3):c.3763C>T (p.Arg1255Trp)

https://sugi.bio/variant/nphp3-p-arg1255trp

## Summary

**NPHP3 p.Arg1255Trp (c.3763C>T)** is classified **Conflicting classifications of pathogenicity** in NPHP3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.1037); Very rare (popmax 0.00848%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs146054765 · 6 submitters · 5 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00848%, nfe)

## For patients & families {#patients}

This is a change in the NPHP3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Inborn genetic diseases.

*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/) |
| Protein change (HGVS p.) | p.Arg1255Trp |
| Coding change (HGVS c.) | c.3763C>T |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| dbSNP | [rs146054765](https://www.ncbi.nlm.nih.gov/snp/rs146054765/) |
| Variant type | single nucleotide variant |
| Location | chr3:132682752-132682752 (GRCh38) |
| ClinVar | [VCV219480](https://www.ncbi.nlm.nih.gov/clinvar/variation/219480/) |

**All HGVS expressions:** `NC_000003.11:g.132401596G>A`, `NC_000003.12:g.132682752G>A`, `NG_008130.2:g.44681C>T`, `NM_153240.5:c.3763C>T`, `NR_037804.1:n.3769C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1037)
- REVEL 0.529 (indeterminate)
- SaProt LLR -8.598 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 6.701, GERP 1.16, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.8**. 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.*
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (132,681,913–132,692,805), spanning 10,892 bp. Chi-square p 0.0019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, 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 **0.00848%** (nfe) · FAF95 0.00708% · FAF99 0.0066% · 100/1,179,598 in the highest group · 126/1,613,464 alleles overall — very rare (popmax 0.00848%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0642% | 1,558 |
| European (non-Finnish) (grpmax) | 0.00848% | 11,796 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,618 |
| African / African-American | 0.00267% | 37,440 |
| South Asian | 0.0011% | 91,076 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-04.

**Submitter consensus:** conflicting (7 Uncertain significance, 1 Likely benign).

**Submission history:** 8 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-04 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-03-19 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-25 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-01-18 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-06-11 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [renal-hepatic-pancreatic dysplasia 1](https://sugi.bio/atlas/disease/renal-hepatic-pancreatic-dysplasia-1/), [NPHP3-related Meckel-like syndrome](https://sugi.bio/atlas/disease/nphp3-related-meckel-like-syndrome/), [nephronophthisis 3](https://sugi.bio/atlas/disease/nephronophthisis-3/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Nephronophthisis, Renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome, not provided, Nephronophthisis 3, Juvenile Nephronophthisis, Adolescent nephronophthisis, GOLDSTON SYNDROME, Meckel syndrome type 7.

## Similar variants {#similar}

Related NPHP3 variant pages (same residue, condition, or type): [NPHP3 p.Arg1255Gln](/variant/nphp3-p-arg1255gln), [NPHP3 c.1985+1G>A](/variant/nphp3-c-1985-plus-1g-a), [NPHP3 c.3201+1G>T](/variant/nphp3-c-3201-plus-1g-t), [NPHP3 c.393+1G>C](/variant/nphp3-c-393-plus-1g-c), [NPHP3 c.520-1G>T](/variant/nphp3-c-520-minus-1g-t), [NPHP3 c.823+1G>T](/variant/nphp3-c-823-plus-1g-t), [NPHP3 c.958-2A>G](/variant/nphp3-c-958-minus-2a-g), [NPHP3 p.Arg1125Ter](/variant/nphp3-p-arg1125ter).

### 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 219480). 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.*