Is NPC1 p.Phe537Ser (c.1610T>C) pathogenic?

NPC1 p.Phe537Ser (c.1610T>C) is classified Uncertain significance in NPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-12-03). AlphaMissense: likely pathogenic (0.7085); Very rare (popmax 0.0022%, sas); Associated with Niemann-Pick disease, type C1.

What condition is associated with NPC1 p.Phe537Ser (c.1610T>C)?

NPC1 p.Phe537Ser (c.1610T>C) is associated with Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Phe537Ser (c.1610T>C) in the general population?

NPC1 p.Phe537Ser (c.1610T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Niemann-Pick disease type C inherited?

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

What do computational predictors say about NPC1 p.Phe537Ser (c.1610T>C)?

AlphaMissense predicts likely pathogenic (score 0.7085) — an in-silico prediction, not a clinical call.

NPC1 p.Phe537Ser

c.1610T>C · rs747310316 · VCV813913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7085 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Niemann-Pick disease, type C1

Computational evidence

Protein change
AlphaMissense	0.7085	likely pathogenic
REVEL	0.769	pathogenic-leaning
SaProt	LLR -10.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,084 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,614,228 alleles · very rare exomes 3/1,461,876 · genomes 0/152,352 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,542
European (non-Finnish)	8.47e-05%	1,180,034

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.Phe537Ser
Coding: c.1610T>C
MANE Select: NM_000271
dbSNP: rs747310316
Type: single nucleotide variant
Location: chr18:23551671 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 537: 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

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 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
NPC1 c.2604+1G>A 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-phe537ser (accessed [today's date]).

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