Is NPC1 p.Arg404Gln (c.1211G>A) pathogenic?

NPC1 p.Arg404Gln (c.1211G>A) is classified Pathogenic in NPC1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.4352); Very rare (popmax 0.005%, amr); Associated with NPC1-related disorder.

What condition is associated with NPC1 p.Arg404Gln (c.1211G>A)?

NPC1 p.Arg404Gln (c.1211G>A) is associated with NPC1-related disorder, Niemann-Pick disease, type C1, Niemann-Pick disease type C (ClinVar).

How common is NPC1 p.Arg404Gln (c.1211G>A) in the general population?

NPC1 p.Arg404Gln (c.1211G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about NPC1 p.Arg404Gln (c.1211G>A)?

AlphaMissense predicts ambiguous (score 0.4352) — an in-silico prediction, not a clinical call.

NPC1 p.Arg404Gln

c.1211G>A · rs139751448 · VCV188794

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

NPC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4352	ambiguous
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -14.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.31	acceptor gain · deltas
Pangolin	Δ0.34	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	34.0	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 0.005% Admixed American · 3/59,992 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00211% 34/1,613,952 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,997
Remaining individualsnot grpmax-eligible	0.0032%	31,243
East Asian	0.00223%	44,874
European (non-Finnish)	0.0022%	45,385
Finnishnot grpmax-eligible	0.00156%	64,022
South Asian	0.0011%	91,080

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.Arg404Gln
Coding: c.1211G>A
MANE Select: NM_000271
dbSNP: rs139751448
Type: single nucleotide variant
Location: chr18:23556358 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 404: a UniProt-annotated variant site (in npc1); a β-strand

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

Disease context

NPC1-related disorder

Also linked: Niemann-Pick disease, type C1 Niemann-Pick disease type C

Similar variants

NPC1 p.Arg404Trp Pathogenic/Likely pathogenic ★★ 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-arg404gln (accessed [today's date]).

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