# NM_153240.5(NPHP3):c.2563C>T (p.Gln855Ter)

https://sugi.bio/variant/nphp3-p-gln855ter

## Summary

**NPHP3 p.Gln855Ter (c.2563C>T)** is classified **Pathogenic/Likely pathogenic** in NPHP3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-06-17). Very rare (popmax 0.00212%, nfe); Associated with NPHP3-related Meckel-like syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs201237799 · 6 submitters · 4 linked conditions · very rare (popmax 0.00212%, nfe)

## For patients & families {#patients}

This is a change in the NPHP3 gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to NPHP3-related Meckel-like syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004665/index) · [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.Gln855Ter |
| Coding change (HGVS c.) | c.2563C>T |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| dbSNP | [rs201237799](https://www.ncbi.nlm.nih.gov/snp/rs201237799/) |
| Variant type | single nucleotide variant |
| Location | chr3:132691199-132691199 (GRCh38) |
| ClinVar | [VCV571559](https://www.ncbi.nlm.nih.gov/clinvar/variation/571559/) |

**All HGVS expressions:** `NC_000003.11:g.132410043G>A`, `NC_000003.12:g.132691199G>A`, `NG_008130.2:g.36234C>T`, `NM_153240.5:c.2563C>T`, `NR_037804.1:n.2569C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.779, GERP 1.57, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.873, pLI 1.4471e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 27**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 43.0**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00212%** (nfe) · FAF95 0.00146% · FAF99 0.00123% · 25/1,176,820 in the highest group · 25/1,610,294 alleles overall — very rare (popmax 0.00212%, 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}

**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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-17.

**Submitter consensus:** conflicting (3 Likely pathogenic, 3 Pathogenic).

**Submission history:** 6 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-04-08 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-06-28 |
| Johns Hopkins Genomics, Johns Hopkins University | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-17 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely pathogenic | criteria provided, single submitter | research | 2023-08-29 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-09-16 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related NPHP3 variant pages (same residue, condition, or type): [NPHP3 p.Gln855Arg](/variant/nphp3-p-gln855arg), [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 571559). 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.*