# NM_000271.5(NPC1):c.1020_1021del (p.Arg341fs)

https://sugi.bio/variant/npc1-p-arg341fs

## Summary

**NPC1 p.Arg341fs (c.1020_1021del)** is classified **Pathogenic/Likely pathogenic** in NPC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-26). No gnomAD frequency available for this variant; Associated with Niemann-Pick disease, type C1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1555637255 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the NPC1 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Niemann-Pick disease, type C1.

*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 | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NPC1 is a diagnostic-grade gene on 22 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/0024693/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NPC1](https://sugi.bio/atlas/gene/NPC1/) |
| Protein change (HGVS p.) | p.Arg341fs |
| Coding change (HGVS c.) | c.1020_1021del |
| MANE Select transcript | [NM_000271](https://www.ncbi.nlm.nih.gov/nuccore/NM_000271) |
| dbSNP | [rs1555637255](https://www.ncbi.nlm.nih.gov/snp/rs1555637255/) |
| Variant type | Microsatellite |
| Location | chr18:23556548-23556549 (GRCh38) |
| ClinVar | [VCV451826](https://www.ncbi.nlm.nih.gov/clinvar/variation/451826/) |

**All HGVS expressions:** `NC_000018.10:g.23556549TG[1]`, `NC_000018.9:g.21136513TG[1]`, `NG_012795.1:g.35067AC[1]`, `NM_000271.5:c.1020_1021del`

## 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 -2.263, GERP -3.28 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.676, pLI 6.0265e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 25**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**NPC1** population constraint: LOEUF 0.676, pLI 6.0265e-11, missense-Z 1.7197. *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 C1** — Definitive (AR)

## Protein context {#protein}

Residue **341** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 85.35, 46% of residues very-high.

**20 experimental structure(s)** (PDB): [3GKH](https://www.rcsb.org/structure/3GKH), [3GKI](https://www.rcsb.org/structure/3GKI), [3GKJ](https://www.rcsb.org/structure/3GKJ), [3JD8](https://www.rcsb.org/structure/3JD8), [5F18](https://www.rcsb.org/structure/5F18), [5F1B](https://www.rcsb.org/structure/5F1B).

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

*Describes the biological roles of NPC1 (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:** NPC1's established molecular role includes cholesterol transfer activity.


### Pathways affected {#pathways}

NPC1 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** cholesterol transfer activity.

**Biological process:** autophagy, glycoprotein biosynthetic process, cholesterol transport, membrane raft organization, intracellular lipid transport, intracellular cholesterol transport.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-03-26.

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

**Submission history:** 2 submissions (2017–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-08-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-26 |

## Associated conditions {#conditions}

[Niemann-Pick disease, type C1](https://sugi.bio/atlas/disease/niemann-pick-disease-type-c1/).

**Reported phenotype names (ClinVar):** Niemann-Pick disease, type C1, not provided, none provided, NEUROVISCERAL STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, NIEMANN-PICK DISEASE WITH CHOLESTEROL ESTERIFICATION BLOCK, NIEMANN-PICK DISEASE WITHOUT SPHINGOMYELINASE DEFICIENCY, NIEMANN-PICK DISEASE, CHRONIC NEURONOPATHIC FORM, NIEMANN-PICK DISEASE, VARIANT TYPE C1.

## Similar variants {#similar}

Related NPC1 variant pages (same residue, condition, or type): [NPC1 p.Arg341Cys](/variant/npc1-p-arg341cys), [NPC1 p.Arg341Pro](/variant/npc1-p-arg341pro), [NPC1 p.Arg341=](/variant/npc1-p-arg341), [NPC1 c.1757_1757+1del](/variant/npc1-c-1757-1757-plus-1del), [NPC1 p.Gln119fs](/variant/npc1-p-gln119fs), [NPC1 p.Ser151fs](/variant/npc1-p-ser151fs), [NPC1 p.Trp381fs](/variant/npc1-p-trp381fs), [NPC1 c.3592-7_3592-5del](/variant/npc1-c-3592-minus-7-3592-minus-5del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 451826). 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.*