# NM_001128178.3(NPHP1):c.127C>T (p.Gln43Ter)

https://sugi.bio/variant/nphp1-p-gln43ter

## Summary

**NPHP1 p.Gln43Ter (c.127C>T)** is classified **Pathogenic/Likely pathogenic** in NPHP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-23). Absent from gnomAD v4.1; Associated with Joubert syndrome with renal defect.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2467599617 · 3 submitters · 4 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the NPHP1 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to Joubert syndrome with renal defect.

*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/0010169/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPHP1](https://sugi.bio/atlas/gene/NPHP1/) |
| Protein change (HGVS p.) | p.Gln43Ter |
| Coding change (HGVS c.) | c.127C>T |
| MANE Select transcript | [NM_001128178](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128178) |
| dbSNP | [rs2467599617](https://www.ncbi.nlm.nih.gov/snp/rs2467599617/) |
| Variant type | single nucleotide variant |
| Location | chr2:110201437-110201437 (GRCh38) |
| ClinVar | [VCV2677274](https://www.ncbi.nlm.nih.gov/clinvar/variation/2677274/) |

**All HGVS expressions:** `NC_000002.11:g.110959014G>A`, `NC_000002.12:g.110201437G>A`, `NG_008287.1:g.8626C>T`, `NM_000272.4:c.127C>T`, `NM_000272.5:c.127C>T`, `NM_001128178.3:c.127C>T`, `NM_001128179.3:c.127C>T`, `NM_001374256.1:c.127C>T`, `NM_001374257.1:c.127C>T`, `NM_207181.4:c.127C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.25) — consistent with the pathogenic call
- Conservation: phyloP 1.356, GERP -0.232, phastCons 0.002 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.92, pLI 4.482e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 20**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 16 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**0.48** (loss), gain 0.00 / loss 0.48. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**NPHP1** population constraint: LOEUF 0.92, pLI 4.482e-10, missense-Z 0.65749. *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 1** — Definitive (AR)

## Protein context {#protein}

Residue **43** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 76.22, 45% of residues very-high.

**2 experimental structure(s)** (PDB): [1S1N](https://www.rcsb.org/structure/1S1N), [6O1Q](https://www.rcsb.org/structure/6O1Q).

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

*Describes the biological roles of NPHP1 (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}

NPHP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |

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

**Biological process:** positive regulation of bicellular tight junction assembly.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-23.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-01-03 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-19 |

## Associated conditions {#conditions}

[Joubert syndrome with renal defect](https://sugi.bio/atlas/disease/joubert-syndrome-with-renal-defect/), [nephronophthisis 1](https://sugi.bio/atlas/disease/nephronophthisis-1/), [Senior-Loken syndrome 1](https://sugi.bio/atlas/disease/senior-loken-syndrome-1/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Joubert syndrome with renal defect, Nephronophthisis, Nephronophthisis 1, Senior-Loken syndrome 1, JOUBERT SYNDROME 4, JUVENILE NEPHRONOPHTHISIS WITH LEBER AMAUROSIS, Nephronophthisis familial juvenile, Juvenile Nephronophthisis.

## Similar variants {#similar}

Related NPHP1 variant pages (same residue, condition, or type): [NPHP1 c.1083+1G>A](/variant/nphp1-c-1083-plus-1g-a), [NPHP1 c.1270-1G>A](/variant/nphp1-c-1270-minus-1g-a), [NPHP1 c.1270-2A>G](/variant/nphp1-c-1270-minus-2a-g), [NPHP1 c.143+1G>C](/variant/nphp1-c-143-plus-1g-c), [NPHP1 c.144-1G>A](/variant/nphp1-c-144-minus-1g-a), [NPHP1 c.1716+1G>T](/variant/nphp1-c-1716-plus-1g-t), [NPHP1 c.329+1G>A](/variant/nphp1-c-329-plus-1g-a), [NPHP1 c.522+1G>A](/variant/nphp1-c-522-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 2677274). 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.*