# NM_001128178.3(NPHP1):c.867A>G (p.Gln289=)

https://sugi.bio/variant/nphp1-p-gln289

## Summary

**NPHP1 p.Gln289= (c.867A>G)** is classified **Conflicting classifications of pathogenicity** in NPHP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-09). Ultra-rare (popmax 0.0454%, afr); Associated with nephronophthisis.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs371112962 · 5 submitters · 4 linked conditions · ultra-rare (popmax 0.0454%, afr)

## For patients & families {#patients}

This is a change in the NPHP1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to nephronophthisis.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NPHP1 is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Nephronophthisis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Abnormality of retinal pigmentation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000206/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.Gln289= |
| Coding change (HGVS c.) | c.867A>G |
| MANE Select transcript | [NM_001128178](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128178) |
| dbSNP | [rs371112962](https://www.ncbi.nlm.nih.gov/snp/rs371112962/) |
| Variant type | single nucleotide variant |
| Location | chr2:110161690-110161690 (GRCh38) |
| ClinVar | [VCV193569](https://www.ncbi.nlm.nih.gov/clinvar/variation/193569/) |

**All HGVS expressions:** `NC_000002.11:g.110919267T>C`, `NC_000002.12:g.110161690T>C`, `NG_008287.1:g.48373A>G`, `NM_000272.5:c.1035A>G`, `NM_001128178.3:c.867A>G`, `NM_001128179.3:c.678A>G`, `NM_001374256.1:c.864A>G`, `NM_001374257.1:c.867A>G`, `NM_207181.4:c.1032A>G`

## 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 **acceptor gain** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -6.433, GERP -2.93 — fast-evolving / accelerated position
- CADD: **PHRED 4.355**. 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 **0.04**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0454%** (afr) · FAF95 0.0334% · FAF99 0.0292% · 34/74,828 in the highest group · 86/1,609,564 alleles overall — ultra-rare (popmax 0.0454%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0454% | 2,201 |
| Admixed American | 0.0283% | 3,528 |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,666 |
| Middle Eastern | 0.0164% | 6,080 |
| East Asian | 0.00223% | 44,808 |
| European (non-Finnish) | 0.00187% | 53,460 |

*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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-09.

**Submitter consensus:** conflicting (4 Uncertain significance, 3 Likely benign).

**Submission history:** 7 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-01-12 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-09 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2021-01-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Nephronophthisis, not provided, Joubert syndrome with renal defect, Senior-Loken syndrome 1, Nephronophthisis 1, not specified, Juvenile Nephronophthisis, AllHighlyPenetrant, none provided, JOUBERT SYNDROME 4.

## Same-residue context {#hotspot}

Residue **289** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NPHP1 p.Gln289Ter](/variant/nphp1-p-gln289ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NPHP1 variant pages (same residue, condition, or type): [NPHP1 p.Gln289Ter](/variant/nphp1-p-gln289ter), [NPHP1 p.Gln289Pro](/variant/nphp1-p-gln289pro), [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).

### 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 193569). 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.*