# NM_015102.5(NPHP4):c.3364A>C (p.Thr1122Pro)

https://sugi.bio/variant/nphp4-p-thr1122pro

## Summary

**NPHP4 p.Thr1122Pro (c.3364A>C)** is classified **Conflicting classifications of pathogenicity** in NPHP4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.3299); Ultra-rare (popmax 0.0184%, nfe); Associated with Senior-Loken syndrome 4.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs375836844 · 7 submitters · 3 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0184%, nfe)

## For patients & families {#patients}

This is a change in the NPHP4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to Senior-Loken syndrome 4.

*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, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Diagnostic panels | NPHP4 is a diagnostic-grade gene on 13 Genomics England panels |

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

- Visual impairment — Very frequent (99-80%)
- Retinal dystrophy — Very frequent (99-80%)
- Hypertension — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Stage 5 chronic kidney disease — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Chronic kidney disease — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015406/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPHP4](https://sugi.bio/atlas/gene/NPHP4/) |
| Protein change (HGVS p.) | p.Thr1122Pro |
| Coding change (HGVS c.) | c.3364A>C |
| MANE Select transcript | [NM_015102](https://www.ncbi.nlm.nih.gov/nuccore/NM_015102) |
| dbSNP | [rs375836844](https://www.ncbi.nlm.nih.gov/snp/rs375836844/) |
| Variant type | single nucleotide variant |
| Location | chr1:5867848-5867848 (GRCh38) |
| ClinVar | [VCV501425](https://www.ncbi.nlm.nih.gov/clinvar/variation/501425/) |

**All HGVS expressions:** `NC_000001.10:g.5927908T>G`, `NC_000001.11:g.5867848T>G`, `NG_011724.2:g.129624A>C`, `NM_001291593.2:c.1825A>C`, `NM_001291594.2:c.1828A>C`, `NM_015102.5:c.3364A>C`, `NR_111987.2:n.4131A>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3299)
- REVEL 0.469 (indeterminate)
- SaProt LLR -11.745 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 1.756, GERP -0.612, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 21.9**. 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 1.02** across the covering region of the MANE Select transcript (5,863,268–5,986,289), spanning 123,021 bp. Chi-square p 0.49. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.0184%** (nfe) · FAF95 0.0164% · FAF99 0.0156% · 217/1,179,838 in the highest group · 226/1,613,702 alleles overall — ultra-rare (popmax 0.0184%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0184% | 5,437 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,808 |
| Admixed American | 0.00167% | 60,002 |

*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}

**NPHP4** population constraint: LOEUF 1.183, pLI 1.9288e-50, missense-Z -0.325. *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 4** — Definitive (AR)

## Protein context {#protein}

Residue **1122** lies in the 'sufficient for basal bodies localization' region.

AlphaFold model confidence (whole protein): pLDDT 72.44, 17% of residues very-high.

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

*Describes the biological roles of NPHP4 (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}

NPHP4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Signaling by Hippo](https://reactome.org/content/detail/R-HSA-2028269) | curated |

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

**Biological process:** negative regulation of canonical Wnt signaling pathway, positive regulation of bicellular tight junction assembly.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-01.

**Submitter consensus:** conflicting (5 Uncertain significance, 1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 7 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-04 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-21 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-10-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-01 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-29 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-09-20 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-29 |

## Associated conditions {#conditions}

[Senior-Loken syndrome 4](https://sugi.bio/atlas/disease/senior-loken-syndrome-4/), [nephronophthisis 4](https://sugi.bio/atlas/disease/nephronophthisis-4/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Senior-Loken syndrome 4, not provided, NPHP4-related disorder, Nephronophthisis, Nephronophthisis 4, NPHP4-related condition, NPHP4-related disorders, NEPHRONOPHTHISIS 4, JUVENILE, none provided, Juvenile Nephronophthisis.

## Similar variants {#similar}

Related NPHP4 variant pages (same residue, condition, or type): [NPHP4 p.Thr1122=](/variant/nphp4-p-thr1122), [NPHP4 c.2304+1G>A](/variant/nphp4-c-2304-plus-1g-a), [NPHP4 c.2611+1G>A](/variant/nphp4-c-2611-plus-1g-a), [NPHP4 c.2611+1G>C](/variant/nphp4-c-2611-plus-1g-c), [NPHP4 c.3644+1G>A](/variant/nphp4-c-3644-plus-1g-a), [NPHP4 c.3644+1G>T](/variant/nphp4-c-3644-plus-1g-t), [NPHP4 c.517+1G>A](/variant/nphp4-c-517-plus-1g-a), [NPHP4 c.518-2A>G](/variant/nphp4-c-518-minus-2a-g).

### 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 501425). 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.*