Is NPC1 p.Phe1207Ser (c.3620T>C) pathogenic?

NPC1 p.Phe1207Ser (c.3620T>C) is classified Conflicting classifications of pathogenicity in NPC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-11). AlphaMissense: likely pathogenic (0.6032); Very rare (popmax 0.00356%, nfe); Associated with Silver-Russell syndrome.

What condition is associated with NPC1 p.Phe1207Ser (c.3620T>C)?

NPC1 p.Phe1207Ser (c.3620T>C) is associated with Silver-Russell syndrome, Niemann-Pick disease, type C1 (ClinVar).

How common is NPC1 p.Phe1207Ser (c.3620T>C) in the general population?

NPC1 p.Phe1207Ser (c.3620T>C) is very rare (popmax 0.00356%, nfe) (gnomAD).

How is Silver-Russell syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPC1 p.Phe1207Ser (c.3620T>C)?

AlphaMissense predicts likely pathogenic (score 0.6032) — an in-silico prediction, not a clinical call.

NPC1 p.Phe1207Ser

c.3620T>C · rs764991360 · VCV1427385

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6032 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Silver-Russell syndrome

Computational evidence

Protein change
AlphaMissense	0.6032	likely pathogenic
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 54 kb · p 0.0029 · regional, not allelic
Overall
CADD	28.4	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

Grpmax group 0.00356% European (non-Finnish) · 42/1,180,050 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00266% 43/1,614,126 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,096
African / African-American	0.00133%	74,934

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.Phe1207Ser
Coding: c.3620T>C
MANE Select: NM_000271
dbSNP: rs764991360
Type: single nucleotide variant
Location: chr18:23533489 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 20 PDB
Residue 1207: an α-helix

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

Disease context

Silver-Russell syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Niemann-Pick disease, type C1

For Silver-Russell syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Antenatal, Neonatal
Prevalence: 1-5 / 10 000 (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-phe1207ser (accessed [today's date]).

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