# NM_001128178.3(NPHP1):c.1721C>T (p.Ser574Leu)

https://sugi.bio/variant/nphp1-p-ser574leu

## Summary

**NPHP1 p.Ser574Leu (c.1721C>T)** is classified **Uncertain significance** in NPHP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-09). AlphaMissense: likely benign (0.0856); Ultra-rare (popmax 0.0421%, nfe); Associated with nephronophthisis 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs138181219 · 5 submitters · 4 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0421%, nfe)

## For patients & families {#patients}

This is a change in the NPHP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 submitters, and is linked to nephronophthisis 1.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018645/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.Ser574Leu |
| Coding change (HGVS c.) | c.1721C>T |
| MANE Select transcript | [NM_001128178](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128178) |
| dbSNP | [rs138181219](https://www.ncbi.nlm.nih.gov/snp/rs138181219/) |
| Variant type | single nucleotide variant |
| Location | chr2:110125677-110125677 (GRCh38) |
| ClinVar | [VCV330728](https://www.ncbi.nlm.nih.gov/clinvar/variation/330728/) |

**All HGVS expressions:** `NC_000002.11:g.110883254G>A`, `NC_000002.12:g.110125677G>A`, `NG_008287.1:g.84386C>T`, `NM_000272.4:c.1889C>T`, `NM_000272.5:c.1889C>T`, `NM_001128178.3:c.1721C>T`, `NM_001128179.3:c.1532C>T`, `NM_001374256.1:c.1718C>T`, `NM_001374257.1:c.1721C>T`, `NM_207181.4:c.1886C>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** (0.0856)
- REVEL 0.092 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.738 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.438, GERP 0.493, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S629L** vs ClinVar **S574L**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.1**. 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 0.96** across the covering region of the MANE Select transcript (110,123,794–110,204,968), spanning 81,174 bp. Chi-square p 0.26. 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, Δ0.47 acceptor 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 **0.0421%** (nfe) · FAF95 0.039% · FAF99 0.0379% · 497/1,179,136 in the highest group · 552/1,612,702 alleles overall — ultra-rare (popmax 0.0421%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.122% | 822 |
| European (non-Finnish) (grpmax) | 0.0421% | 2,373 |
| Remaining individuals (not grpmax-eligible) | 0.0224% | 4,463 |
| East Asian | 0.00446% | 22,424 |
| Admixed American | 0.00167% | 59,998 |
| Finnish (not grpmax-eligible) | 0.00157% | 63,646 |
| African / African-American | 0.00133% | 74,988 |

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}

**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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-09.

**Submitter consensus:** unanimous (7/7 Uncertain significance).

**Submission history:** 7 submissions (2018–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-06 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-09-05 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-09 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-28 |

## Associated conditions {#conditions}

[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/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Nephronophthisis 1, Senior-Loken syndrome 1, Joubert syndrome with renal defect, Nephronophthisis, NPHP1-related disorder, not provided, Nephronophthisis familial juvenile, JUVENILE NEPHRONOPHTHISIS WITH LEBER AMAUROSIS, JOUBERT SYNDROME 4, none provided.

## Similar variants {#similar}

Related NPHP1 variant pages (same residue, condition, or type): [NPHP1 p.Ser574=](/variant/nphp1-p-ser574), [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).

### 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 330728). 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.*