# NM_006432.5(NPC2):c.120C>T (p.Ser40=)

https://sugi.bio/variant/npc2-p-ser40

## Summary

**NPC2 p.Ser40= (c.120C>T)** is classified **Likely benign** in NPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). No allele count reported in gnomAD v4.1 (AN 1,603,768); Associated with Niemann-Pick disease, type C2.

**At a glance:** Likely benign · review: Single submitter · rsID rs2506107274 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,603,768)

## 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, and is linked to Niemann-Pick disease, type C2.

*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) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NPC2 is a diagnostic-grade gene on 20 Genomics England panels |

**Commonly reported features of Niemann-Pick disease type C** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Vertical supranuclear gaze palsy — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Jaundice — Very frequent (99-80%)
- Mental deterioration — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Abnormality of the liver — Very frequent (99-80%)
- Dysphagia — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003992/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPC2](https://sugi.bio/atlas/gene/NPC2/) |
| Protein change (HGVS p.) | p.Ser40= |
| Coding change (HGVS c.) | c.120C>T |
| MANE Select transcript | [NM_006432](https://www.ncbi.nlm.nih.gov/nuccore/NM_006432) |
| dbSNP | [rs2506107274](https://www.ncbi.nlm.nih.gov/snp/rs2506107274/) |
| Variant type | single nucleotide variant |
| Location | chr14:74486399-74486399 (GRCh38) |
| ClinVar | [VCV2101775](https://www.ncbi.nlm.nih.gov/clinvar/variation/2101775/) |

**All HGVS expressions:** `NC_000014.8:g.74953102G>A`, `NC_000014.9:g.74486399G>A`, `NG_007117.1:g.11983C>T`, `NM_001363688.1:c.120C>T`, `NM_001375440.1:c.120C>T`, `NM_006432.5:c.120C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.39) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.782, GERP 0.86, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.01**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.39**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.39**.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,603,768)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

Residue **40** lies in a β-strand.

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 2023-11-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-27 |

## Associated conditions {#conditions}

[Niemann-Pick disease, type C2](https://sugi.bio/atlas/disease/niemann-pick-disease-type-c2/).

**Reported phenotype names (ClinVar):** Niemann-Pick disease, type C2.

## Same-residue context {#hotspot}

Residue **40** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NPC2 p.Ser40Ter](/variant/npc2-p-ser40ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NPC2 variant pages (same residue, condition, or type): [NPC2 p.Ser40Ter](/variant/npc2-p-ser40ter), [NPC2 c.190+5G>A](/variant/npc2-c-190-plus-5g-a), [NPC2 p.Cys47Ter](/variant/npc2-p-cys47ter), [NPC2 p.Cys99Arg](/variant/npc2-p-cys99arg), [NPC2 p.Gln45Ter](/variant/npc2-p-gln45ter), [NPC2 p.Glu118Ter](/variant/npc2-p-glu118ter), [NPC2 p.Glu20Ter](/variant/npc2-p-glu20ter), [NPC2 p.Met1Ile](/variant/npc2-p-met1ile).

### 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 2101775). 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.*