Is NPC1 p.Pro237Ser (c.709C>T) pathogenic?

NPC1 p.Pro237Ser (c.709C>T) is classified Conflicting classifications of pathogenicity in NPC1 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1037); Low-frequency (popmax 1.61%, nfe); Associated with nasopharyngeal carcinoma.

What condition is associated with NPC1 p.Pro237Ser (c.709C>T)?

NPC1 p.Pro237Ser (c.709C>T) is associated with nasopharyngeal carcinoma, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Pro237Ser (c.709C>T) in the general population?

NPC1 p.Pro237Ser (c.709C>T) is low-frequency (popmax 1.61%, nfe) (gnomAD).

How is Nasopharyngeal carcinoma inherited?

Typically Multigenic/multifactorial, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPC1 p.Pro237Ser (c.709C>T)?

AlphaMissense predicts likely benign (score 0.1037) — an in-silico prediction, not a clinical call.

NPC1 p.Pro237Ser

c.709C>T · rs80358251 · VCV21142

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.1037 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.61%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nasopharyngeal carcinoma

Computational evidence

Protein change
AlphaMissense	0.1037	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	21.2	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 1.61% European (non-Finnish) · 19,049/1,179,998 alleles

Filtering AF 1.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.59%

Overall 1.34% 21,697/1,614,168 alleles · low-frequency exomes 20,169/1,461,824 · genomes 1,528/152,344 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.96%	51
European (non-Finnish)grpmax	1.61%	62
Remaining individualsnot grpmax-eligible	1.18%	85
Admixed American	0.453%	221
Ashkenazi Jewishnot grpmax-eligible	0.331%	302
African / African-American	0.248%	404
Middle Eastern	0.165%	605
South Asian	0.102%	979
East Asian	0.00223%	44,886

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro237Ser
Coding: c.709C>T
MANE Select: NM_000271
dbSNP: rs80358251
Type: single nucleotide variant
Location: chr18:23560403 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 237: an α-helix; a UniProt-annotated variant site (no effect on function; colocalizes with the wild-type protein with rab7-positive late endosomes; clears the lysosomal cholesterol accumulation in npc1-deficient cells)

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

Disease context

nasopharyngeal carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Niemann-Pick disease, type C1

For Nasopharyngeal carcinoma (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (China)

Similar variants

NPC1 p.Pro237= Likely benign ★ same residue
NPC1 p.Pro237Leu Uncertain significance ★ ⚠ 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

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-pro237ser (accessed [today's date]).

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