Is NPC2 p.Thr44Pro (c.130A>C) pathogenic?

NPC2 p.Thr44Pro (c.130A>C) is classified Uncertain significance in NPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.3067); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with NPC2 p.Thr44Pro (c.130A>C)?

NPC2 p.Thr44Pro (c.130A>C) is associated with Inborn genetic diseases (ClinVar).

How common is NPC2 p.Thr44Pro (c.130A>C) in the general population?

NPC2 p.Thr44Pro (c.130A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPC2 p.Thr44Pro (c.130A>C)?

AlphaMissense predicts likely benign (score 0.3067) — an in-silico prediction, not a clinical call.

NPC2 p.Thr44Pro

c.130A>C · rs2139670146 · VCV1769606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3067 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3067	likely benign
REVEL	0.358	indeterminate
SaProt	LLR -12.01	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.24	GERP -1.7
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	20.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPC2
Protein: p.Thr44Pro
Coding: c.130A>C
MANE Select: NM_006432
dbSNP: rs2139670146
Type: single nucleotide variant
Location: chr14:74486389 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 2 PDB

Full NPC2 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

Similar variants

NPC2 p.Thr44Ile Uncertain significance ★ ⚠ same residue
NPC2 p.Thr44= Likely benign ★ same residue
NPC2 p.Cys47Ter Pathogenic ★★ same condition
NPC2 p.Glu20Ter Pathogenic ★★ same condition
NPC2 p.Asn98His Uncertain significance ★★ ⚠ same condition
NPC2 p.Asp91Asn Uncertain significance ★★ ⚠ same condition
NPC2 p.Gln102Arg Uncertain significance ★★ ⚠ same condition
NPC2 p.Gln136Glu Uncertain significance ★★ ⚠ 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-thr44pro (accessed [today's date]).

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