Is NPC2 p.Pro41= (c.123A>G) pathogenic?

NPC2 p.Pro41= (c.123A>G) is classified Likely benign in NPC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-16). Very rare (popmax 0.00223%, eas); Associated with Niemann-Pick disease, type C2.

What condition is associated with NPC2 p.Pro41= (c.123A>G)?

NPC2 p.Pro41= (c.123A>G) is associated with Niemann-Pick disease, type C2 (ClinVar).

How common is NPC2 p.Pro41= (c.123A>G) in the general population?

NPC2 p.Pro41= (c.123A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Niemann-Pick disease type C inherited?

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

NPC2 p.Pro41=

c.123A>G · rs766219527 · VCV2450709

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Niemann-Pick disease, type C2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.1	GERP -3.8
Overall
CADD	1.699	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,812 alleles

Filtering AF 0.000248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000499% 8/1,604,620 alleles · very rare exomes 8/1,452,328 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,812
European (non-Finnish)	0.000596%	167,918

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: NPC2
Protein: p.Pro41=
Coding: c.123A>G
MANE Select: NM_006432
dbSNP: rs766219527
Type: single nucleotide variant
Location: chr14:74486396 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB
Residue 41: a β-strand

Full NPC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Niemann-Pick disease, type C2 — 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

NPC2 c.190+5G>A Pathogenic/Likely pathogenic ★★ same condition
NPC2 p.Cys47Ter Pathogenic ★★ same condition
NPC2 p.Cys99Arg Pathogenic ★★ same condition
NPC2 p.Gln45Ter Pathogenic/Likely pathogenic ★★ same condition
NPC2 p.Glu118Ter Pathogenic ★★ same condition
NPC2 p.Glu20Ter Pathogenic ★★ same condition
NPC2 p.Met1Ile Pathogenic/Likely pathogenic ★★ same condition
NPC2 p.Pro120Ser 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/npc2-p-pro41 (accessed [today's date]).

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