Is NPC1 p.Thr477= (c.1431G>A) pathogenic?

NPC1 p.Thr477= (c.1431G>A) is classified Conflicting classifications of pathogenicity in NPC1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0758%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPC1 p.Thr477= (c.1431G>A)?

NPC1 p.Thr477= (c.1431G>A) is associated with Inborn genetic diseases, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Thr477= (c.1431G>A) in the general population?

NPC1 p.Thr477= (c.1431G>A) is ultra-rare (popmax 0.0758%, eas) (gnomAD).

NPC1 p.Thr477=

c.1431G>A · rs375307057 · VCV500155

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0758%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP 1.4, phastCons 0.011
Overall
CADD	12.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0758% East Asian · 34/44,882 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0488%

Overall 0.0191% 309/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0758%	1,320
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,700
South Asian	0.0209%	4,793
European (non-Finnish)	0.0179%	5,592
Admixed American	0.0167%	6,002
Middle Eastern	0.0165%	6,062

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.Thr477=
Coding: c.1431G>A
MANE Select: NM_000271
dbSNP: rs375307057
Type: single nucleotide variant
Location: chr18:23554880 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 477: a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Niemann-Pick disease, type C1

Similar variants

NPC1 p.Thr477Met Conflicting classifications of pathogenicity ★ ⚠ 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-thr477 (accessed [today's date]).

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