# NM_001128178.3(NPHP1):c.14G>T (p.Arg5Leu)

https://sugi.bio/variant/nphp1-p-arg5leu

## Summary

**NPHP1 p.Arg5Leu (c.14G>T)** is classified **Benign/Likely benign** in NPHP1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.2856); Low-frequency (popmax 4.49%, amr); Associated with intellectual disability, X-linked 102.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs190983114 · 12 submitters · 6 linked conditions · AlphaMissense likely benign · low-frequency (popmax 4.49%, amr)

## For patients & families {#patients}

This is a change in the NPHP1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 12 submitters, and is linked to intellectual disability, X-linked 102.

*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/0024730/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.Arg5Leu |
| Coding change (HGVS c.) | c.14G>T |
| MANE Select transcript | [NM_001128178](https://www.ncbi.nlm.nih.gov/nuccore/NM_001128178) |
| dbSNP | [rs190983114](https://www.ncbi.nlm.nih.gov/snp/rs190983114/) |
| Variant type | single nucleotide variant |
| Location | chr2:110204955-110204955 (GRCh38) |
| ClinVar | [VCV129814](https://www.ncbi.nlm.nih.gov/clinvar/variation/129814/) |

**All HGVS expressions:** `NC_000002.11:g.110962532C>A`, `NC_000002.12:g.110204955C>A`, `NG_008287.1:g.5108G>T`, `NM_000272.4:c.14G>T`, `NM_000272.5:c.14G>T`, `NM_001128178.3:c.14G>T`, `NM_001128179.3:c.14G>T`, `NM_001374256.1:c.14G>T`, `NM_001374257.1:c.14G>T`, `NM_207181.4:c.14G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2856)
- REVEL 0.203 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.576 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.899, GERP -0.198, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 20.4**. 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: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **4.49%** (amr) · FAF95 4.35% · FAF99 4.29% · 2,694/60,026 in the highest group · 2,933/1,614,002 alleles overall — low-frequency (popmax 4.49%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 4.49% | 22 |
| Remaining individuals (not grpmax-eligible) | 0.176% | 568 |
| African / African-American | 0.0959% | 1,042 |
| Middle Eastern | 0.0165% | 6,050 |
| South Asian | 0.011% | 9,107 |
| European (non-Finnish) | 0.0039% | 25,651 |

*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 **5** lies in a UniProt-annotated variant site (changed function; unable to rescue the corresponding loss of function zebrafish mutant which displays a cilium function alteration phenotype).

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (9 Benign, 5 Likely benign).

**Submission history:** 14 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Benign | criteria provided, single submitter | research |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-09-18 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2024-10-23 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-02-04 |

## Associated conditions {#conditions}

[intellectual disability, X-linked 102](https://sugi.bio/atlas/disease/intellectual-disability-x-linked-102/), [Joubert syndrome 1](https://sugi.bio/atlas/disease/joubert-syndrome-1/), [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):** Intellectual disability, X-linked 102, not specified, Nephronophthisis, Joubert syndrome with renal defect, Senior-Loken syndrome 1, Joubert syndrome 1, Nephronophthisis 1, not provided, Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, Juvenile Nephronophthisis.

## Similar variants {#similar}

Related NPHP1 variant pages (same residue, condition, or type): [NPHP1 p.Arg5Pro](/variant/nphp1-p-arg5pro), [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 2026-10-15); 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 129814). 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.*