# NM_000271.5(NPC1):c.2777C>T (p.Ala926Val)

https://sugi.bio/variant/npc1-p-ala926val

## Summary

**NPC1 p.Ala926Val (c.2777C>T)** is classified **Pathogenic/Likely pathogenic** in NPC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.2678); Very rare (popmax 0.00267%, afr); Associated with Niemann-Pick disease, type C1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs730880963 · 4 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the NPC1 gene that is considered likely disease-causing, submitted by 4 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.Ala926Val |
| Coding change (HGVS c.) | c.2777C>T |
| MANE Select transcript | [NM_000271](https://www.ncbi.nlm.nih.gov/nuccore/NM_000271) |
| dbSNP | [rs730880963](https://www.ncbi.nlm.nih.gov/snp/rs730880963/) |
| Variant type | single nucleotide variant |
| Location | chr18:23539829-23539829 (GRCh38) |
| ClinVar | [VCV181456](https://www.ncbi.nlm.nih.gov/clinvar/variation/181456/) |

**All HGVS expressions:** `NC_000018.10:g.23539829G>A`, `NC_000018.9:g.21119793G>A`, `NG_012795.1:g.51789C>T`, `NM_000271.5:c.2777C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.2678) — ⚠ discordant with the pathogenic call
- REVEL 0.9 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.243 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 11.727, GERP 1.81, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.5**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (23,532,205–23,586,343), spanning 54,138 bp. Chi-square p 0.0029. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,922 in the highest group · 9/1,614,042 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,461 |
| South Asian | 0.0011% | 91,088 |
| European (non-Finnish) | 0.000508% | 196,672 |

*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 **926** lies in a UniProt-annotated variant site (in npc1); 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 2025-10-15.

**Submitter consensus:** conflicting (2 Pathogenic, 2 Likely pathogenic).

**Submission history:** 4 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CENTOGENE GmbH and LLC - Guiding Precision Medicine | Pathogenic | criteria provided, single submitter | clinical testing |  |
| AiLife Diagnostics, AiLife Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-21 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-15 |

## 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.

## Same-residue context {#hotspot}

Residue **926** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NPC1 p.Ala926Thr](/variant/npc1-p-ala926thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NPC1 variant pages (same residue, condition, or type): [NPC1 p.Ala926Thr](/variant/npc1-p-ala926thr), [NPC1 p.Ala926=](/variant/npc1-p-ala926), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 181456). 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.*