# NM_000271.5(NPC1):c.2910A>G (p.Ser970=)

https://sugi.bio/variant/npc1-p-ser970

## Summary

**NPC1 p.Ser970= (c.2910A>G)** is classified **Uncertain significance** in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). No allele count reported in gnomAD v4.1 (AN 1,604,174); Associated with Niemann-Pick disease, type C1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2511209805 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,604,174)

## For patients & families {#patients}

This is a change in the NPC1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Ser970= |
| Coding change (HGVS c.) | c.2910A>G |
| MANE Select transcript | [NM_000271](https://www.ncbi.nlm.nih.gov/nuccore/NM_000271) |
| dbSNP | [rs2511209805](https://www.ncbi.nlm.nih.gov/snp/rs2511209805/) |
| Variant type | single nucleotide variant |
| Location | chr18:23539356-23539356 (GRCh38) |
| ClinVar | [VCV2129690](https://www.ncbi.nlm.nih.gov/clinvar/variation/2129690/) |

**All HGVS expressions:** `NC_000018.10:g.23539356T>C`, `NC_000018.9:g.21119320T>C`, `NG_012795.2:g.52150A>G`, `NM_000271.5:c.2910A>G`

## 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 -2.014, GERP -2.19 — fast-evolving / accelerated position
- CADD: **PHRED 13.01**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for NPC1 (1,277 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,604,174)** — 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 **970** lies in a β-strand.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-25.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-25 |

## 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, NIEMANN-PICK DISEASE, VARIANT TYPE C1, NIEMANN-PICK DISEASE WITHOUT SPHINGOMYELINASE DEFICIENCY, NEUROVISCERAL STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, NIEMANN-PICK DISEASE WITH CHOLESTEROL ESTERIFICATION BLOCK, NIEMANN-PICK DISEASE, CHRONIC NEURONOPATHIC FORM.

## Same-residue context {#hotspot}

Residue **970** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NPC1 p.Ser970fs](/variant/npc1-p-ser970fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NPC1 variant pages (same residue, condition, or type): [NPC1 p.Ser970fs](/variant/npc1-p-ser970fs), [NPC1 c.1554-1009G>A](/variant/npc1-c-1554-minus-1009g-a), [NPC1 c.1757+1G>A](/variant/npc1-c-1757-plus-1g-a), [NPC1 c.1947+5G>C](/variant/npc1-c-1947-plus-5g-c), [NPC1 c.2130+1G>A](/variant/npc1-c-2130-plus-1g-a), [NPC1 c.2245+1G>A](/variant/npc1-c-2245-plus-1g-a), [NPC1 c.2246-2A>G](/variant/npc1-c-2246-minus-2a-g), [NPC1 c.2515-2A>G](/variant/npc1-c-2515-minus-2a-g).

### 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 2129690). 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.*