# NM_153240.5(NPHP3):c.2975C>T (p.Ala992Val)

https://sugi.bio/variant/nphp3-p-ala992val

## Summary

**NPHP3 p.Ala992Val (c.2975C>T)** is classified **Conflicting classifications of pathogenicity** in NPHP3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-10). AlphaMissense: likely pathogenic (0.983); Very rare (popmax 6.2e-05%); Associated with Joubert syndrome and related disorders.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the NPHP3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Joubert syndrome and related disorders.

*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/0019931/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPHP3](https://sugi.bio/atlas/gene/NPHP3/) |
| Protein change (HGVS p.) | p.Ala992Val |
| Coding change (HGVS c.) | c.2975C>T |
| MANE Select transcript | [NM_153240](https://www.ncbi.nlm.nih.gov/nuccore/NM_153240) |
| Variant type | single nucleotide variant |
| Location | chr3:132688800-132688800 (GRCh38) |
| ClinVar | [VCV3764589](https://www.ncbi.nlm.nih.gov/clinvar/variation/3764589/) |

**All HGVS expressions:** `NC_000003.11:g.132407644G>A`, `NC_000003.12:g.132688800G>A`, `NG_008130.2:g.38633C>T`, `NM_153240.5:c.2975C>T`, `NR_037804.1:n.2981C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.983)
- REVEL 0.759 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.87 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.35) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 11.763, GERP 1.74, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in NPHP3 (of 7,784 modeled).
- CADD: **PHRED 34.0**. 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.*
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (132,681,913–132,692,805), spanning 10,892 bp. Chi-square p 0.0019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.35**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.35**.
- Pangolin: Δ**0.48** (gain), gain 0.48 / loss 0.00. 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 (gnomAD v4.1): global (via dbSNP) **6.2e-05%** · 1/1,614,072 alleles overall — very rare (popmax 6.2e-05%).

*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}

**NPHP3** population constraint: LOEUF 0.873, pLI 1.4471e-21, missense-Z 0.91316. *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** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.59, 9% of residues very-high.

**1 experimental structure(s)** (PDB): [5L7K](https://www.rcsb.org/structure/5L7K).

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

*Describes the biological roles of NPHP3 (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}

NPHP3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Trafficking of myristoylated proteins to the cilium](https://reactome.org/content/detail/R-HSA-5624138) | curated |

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

**Biological process:** kidney development, heart looping, atrial septum development, determination of left/right symmetry, lung development, determination of pancreatic left/right asymmetry.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-12-10.

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

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Daryl Scott Lab, Baylor College of Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-10 |

## Associated conditions {#conditions}

[Joubert syndrome and related disorders](https://sugi.bio/atlas/disease/joubert-syndrome-and-related-disorders/).

**Reported phenotype names (ClinVar):** Joubert syndrome and related disorders, NPHP3-related disorder, NPHP3-related disorders, NPHP3-related condition.

## Similar variants {#similar}

Related NPHP3 variant pages (same residue, condition, or type): [NPHP3 p.Arg702Ter](/variant/nphp3-p-arg702ter), [NPHP3 p.Arg951Ter](/variant/nphp3-p-arg951ter), [NPHP3 p.Leu790Pro](/variant/nphp3-p-leu790pro), [NPHP3 p.Tyr1037Ter](/variant/nphp3-p-tyr1037ter), [NPHP3 c.3813-3A>G](/variant/nphp3-c-3813-minus-3a-g), [NPHP3 c.1888-7_1893del](/variant/nphp3-c-1888-minus-7-1893del), [NPHP3 p.Glu435del](/variant/nphp3-p-glu435del), [NPHP3 c.1985+1G>A](/variant/nphp3-c-1985-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 3764589). 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.*