# NM_006432.5(NPC2):c.*252del

https://sugi.bio/variant/npc2-c-star-252del

## Summary

**NPC2 c.*252del** is classified **Likely benign** in NPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-05). Low-frequency (popmax 1.43%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs369932535 · 1 submitter · low-frequency (popmax 1.43%, afr)

## For patients & families {#patients}

This is a change in the NPC2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPC2](https://sugi.bio/atlas/gene/NPC2/) |
| Coding change (HGVS c.) | c.*252del |
| MANE Select transcript | [NM_006432](https://www.ncbi.nlm.nih.gov/nuccore/NM_006432) |
| dbSNP | [rs369932535](https://www.ncbi.nlm.nih.gov/snp/rs369932535/) |
| Variant type | Deletion |
| Location | chr14:74480022-74480022 (GRCh38) |
| ClinVar | [VCV1202055](https://www.ncbi.nlm.nih.gov/clinvar/variation/1202055/) |

**All HGVS expressions:** `NC_000014.8:g.74946734del`, `NC_000014.9:g.74480031del`, `NG_007117.1:g.18360del`, `NM_001363688.1:c.*596del`, `NM_001375440.1:c.*252del`, `NM_006432.5:c.*252del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.545, GERP -0.653, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 1.108**. 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.*
- Non-coding constraint (Gnocchi): **Z 1.78**, o/e 0.87 (1 kb window 74,480,000–74,481,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **1.43%** (afr) · FAF95 1.36% · FAF99 1.33% · 966/67,548 in the highest group · 1,914/1,373,998 alleles overall — low-frequency (popmax 1.43%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.43% | 70 |
| Admixed American | 0.237% | 421 |
| Remaining individuals (not grpmax-eligible) | 0.213% | 469 |
| East Asian | 0.198% | 504 |
| Middle Eastern | 0.169% | 592 |
| Finnish (not grpmax-eligible) | 0.167% | 599 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.12% | 831 |
| South Asian | 0.0872% | 1,146 |
| European (non-Finnish) | 0.0497% | 2,013 |

*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}

**NPC2** population constraint: LOEUF 1.422, pLI 2.2188e-06, missense-Z 0.46551. *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):

- **Niemann-Pick disease, type C2** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.88, 86% of residues very-high.

**2 experimental structure(s)** (PDB): [5KWY](https://www.rcsb.org/structure/5KWY), [6W5V](https://www.rcsb.org/structure/6W5V).

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

*Describes the biological roles of NPC2 (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.*

**How this variant is thought to act:** NPC2's established molecular role includes cholesterol binding.


### Pathways affected {#pathways}

NPC2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [LDL clearance](https://reactome.org/content/detail/R-HSA-8964038) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** cholesterol binding, enzyme binding, cholesterol transfer activity.

**Biological process:** response to virus, cholesterol transport, intracellular sterol transport, intracellular cholesterol transport, cholesterol efflux, cholesterol homeostasis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-07-05.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-07-05 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related NPC2 variant pages (same residue, condition, or type): [NPC2 c.191-1_193del](/variant/npc2-c-191-minus-1-193del), [NPC2 p.Ala5fs](/variant/npc2-p-ala5fs), [NPC2 p.Asn111fs](/variant/npc2-p-asn111fs), [NPC2 p.Asp31fs](/variant/npc2-p-asp31fs), [NPC2 p.Ile97fs](/variant/npc2-p-ile97fs), [NPC2 p.Ser50fs](/variant/npc2-p-ser50fs), [NPC2 p.Thr44fs](/variant/npc2-p-thr44fs), [NPC2 p.Thr62fs](/variant/npc2-p-thr62fs).

### 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 1202055). 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.*