# NM_153240.5(NPHP3):c.2266C>T (p.Arg756Trp)

https://sugi.bio/variant/nphp3-p-arg756trp

## Summary

**NPHP3 p.Arg756Trp (c.2266C>T)** is classified **Uncertain significance** in NPHP3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.1169); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs183049702 · 4 submitters · 5 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.01%, amr)

## For patients & families {#patients}

This is a change in the NPHP3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 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.Arg756Trp |
| Coding change (HGVS c.) | c.2266C>T |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| dbSNP | [rs183049702](https://www.ncbi.nlm.nih.gov/snp/rs183049702/) |
| Variant type | single nucleotide variant |
| Location | chr3:132694871-132694871 (GRCh38) |
| ClinVar | [VCV498139](https://www.ncbi.nlm.nih.gov/clinvar/variation/498139/) |

**All HGVS expressions:** `NC_000003.11:g.132413715G>A`, `NC_000003.12:g.132694871G>A`, `NG_008130.2:g.32562C>T`, `NM_153240.4:c.2266C>T`, `NM_153240.5:c.2266C>T`, `NR_037804.1:n.2272C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1169)
- REVEL 0.27 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.617 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.967, GERP 1.01, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.9**. 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 1.01** across the covering region of the MANE Select transcript (132,692,806–132,722,316), spanning 29,510 bp. Chi-square p 0.87. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.04**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 44 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.23** (loss), gain 0.00 / loss 0.23. 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 **0.01%** (amr) · FAF95 0.00428% · FAF99 0.00295% · 6/59,998 in the highest group · 27/1,613,610 alleles overall — ultra-rare (popmax 0.01%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.01% | 10,000 |
| East Asian | 0.00892% | 11,210 |
| African / African-American | 0.008% | 12,499 |
| South Asian | 0.0022% | 45,535 |
| European (non-Finnish) | 0.000763% | 131,098 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-17.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-10-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-17 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-09 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-03 |

## 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, not provided, Nephronophthisis, NPHP3-related Meckel-like syndrome, Nephronophthisis 3, Renal-hepatic-pancreatic dysplasia 1, Juvenile Nephronophthisis, Adolescent nephronophthisis, GOLDSTON SYNDROME, Meckel syndrome type 7.

## Similar variants {#similar}

Related NPHP3 variant pages (same residue, condition, or type): [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), [NPHP3 p.Arg1259Ter](/variant/nphp3-p-arg1259ter).

### 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 498139). 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.*