Is NPC1 p.Val347= (c.1041C>T) pathogenic?

NPC1 p.Val347= (c.1041C>T) is classified Likely benign in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). Ultra-rare (popmax 0.0111%, eas); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Val347= (c.1041C>T)?

NPC1 p.Val347= (c.1041C>T) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Val347= (c.1041C>T) in the general population?

NPC1 p.Val347= (c.1041C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

How is Niemann-Pick disease type C inherited?

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

NPC1 p.Val347=

c.1041C>T · rs2058954302 · VCV1674992

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -1.7, phastCons 1
Overall
CADD	8.291	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,900 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000496% 8/1,614,052 alleles · ultra-rare exomes 7/1,461,872 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,980
European (non-Finnish)	0.000254%	393,346

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.Val347=
Coding: c.1041C>T
MANE Select: NM_000271
dbSNP: rs2058954302
Type: single nucleotide variant
Location: chr18:23556528 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 347: 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.Val347Ile Uncertain significance ★★ ⚠ 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
NPC1 c.2246-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPC1 c.2515-2A>G 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-val347 (accessed [today's date]).

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