# NM_006432.5(NPC2):c.9C>T (p.Phe3=)

https://sugi.bio/variant/npc2-p-phe3

## Summary

**NPC2 p.Phe3= (c.9C>T)** is classified **Likely benign** in NPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). Very rare (popmax 8.48e-05%, nfe); Associated with Niemann-Pick disease, type C2.

**At a glance:** Likely benign · review: Single submitter · rsID rs1300524708 · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## 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.Phe3= |
| Coding change (HGVS c.) | c.9C>T |
| MANE Select transcript | [NM_006432](https://www.ncbi.nlm.nih.gov/nuccore/NM_006432) |
| dbSNP | [rs1300524708](https://www.ncbi.nlm.nih.gov/snp/rs1300524708/) |
| Variant type | single nucleotide variant |
| Location | chr14:74493266-74493266 (GRCh38) |
| ClinVar | [VCV1080762](https://www.ncbi.nlm.nih.gov/clinvar/variation/1080762/) |

**All HGVS expressions:** `NC_000014.8:g.74959969G>A`, `NC_000014.9:g.74493266G>A`, `NG_007117.1:g.5116C>T`, `NG_033074.1:g.4547G>A`, `NM_001363688.1:c.9C>T`, `NM_001375440.1:c.9C>T`, `NM_006432.5:c.9C>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 (below), not from a missing predictor score.
- Conservation: phyloP 0.735, GERP -0.289 — weakly conserved position
- CADD: **PHRED 10.09**. 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: **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 **8.48e-05%** (nfe) · 1/1,179,692 in the highest group · 1/1,613,232 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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 2023-02-01.

**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 | 2023-02-01 |

## 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.

## Similar variants {#similar}

Related NPC2 variant pages (same residue, condition, or type): [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), [NPC2 p.Pro120Ser](/variant/npc2-p-pro120ser).

### 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 1080762). 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.*