Is NPC1 p.Pro434Leu (c.1301C>T) pathogenic?

NPC1 p.Pro434Leu (c.1301C>T) is classified Pathogenic/Likely pathogenic in NPC1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.1247); Very rare (popmax 0.00401%, afr); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Pro434Leu (c.1301C>T)?

NPC1 p.Pro434Leu (c.1301C>T) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Pro434Leu (c.1301C>T) in the general population?

NPC1 p.Pro434Leu (c.1301C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

How is Niemann-Pick disease type C inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPC1 p.Pro434Leu (c.1301C>T)?

AlphaMissense predicts likely benign (score 0.1247) — an in-silico prediction, not a clinical call.

NPC1 p.Pro434Leu

c.1301C>T · rs774333145 · VCV429322

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
AlphaMissense	0.1247	likely benign ⚠ discordant with ClinVar
REVEL	0.509	indeterminate
SaProt	LLR -8.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,896 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00297% 48/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,965
European (non-Finnish)	0.00356%	28,096
South Asian	0.0022%	45,536
Remaining individualsnot grpmax-eligible	0.0016%	62,480

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NPC1
Protein: p.Pro434Leu
Coding: c.1301C>T
MANE Select: NM_000271
dbSNP: rs774333145
Type: single nucleotide variant
Location: chr18:23556268 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 434: a UniProt-annotated variant site (in npc1); a UniProt-annotated variant site (in); an α-helix

Full NPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Niemann-Pick disease, type C1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Niemann-Pick disease type C (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

NPC1 p.Pro434Ser Benign/Likely benign ★★ ⚠ same residue
NPC1 p.Pro434Arg Uncertain significance ★ ⚠ same residue
NPC1 p.Pro434= Likely benign ★ same residue
NPC1 c.1554-1009G>A Pathogenic ★★ same condition
NPC1 c.1757+1G>A Likely pathogenic ★★ same condition
NPC1 c.1947+5G>C Pathogenic/Likely pathogenic ★★ same condition
NPC1 c.2130+1G>A Pathogenic ★★ same condition
NPC1 c.2245+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/npc1-p-pro434leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown