CYP46A1

Chr 14

cytochrome P450 family 46 subfamily A member 1

Also known as: CP46, CYP46

NCBI Gene: 10858 ENSG00000036530 UniProt: Q9Y6A2 OMIM: 604087

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein is expressed in the brain, where it converts cholesterol to 24S-hydroxycholesterol. While cholesterol cannot pass the blood-brain barrier, 24S-hydroxycholesterol can be secreted in the brain into the circulation to be returned to the liver for catabolism. [provided by RefSeq, Jul 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.986

Z-score 4.19

OE 0.12 (0.05–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.97Z-score

OE missense 0.52 (0.45–0.59)

156 obs / 300.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.05–0.30)

0≤0.351.4

Missense OE?0.52 (0.45–0.59)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 3 / 26.1Missense obs/exp: 156 / 300.9Syn Z: -0.73

Background carrier burden — how many people carry a rare variant somewhere in CYP46A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

487 rare PASS variants

Rare truncating (LoF)

1 in 7,500

44 rare PASS variants

Rare synonymous (reference)

1 in 190

293 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CYP46A1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 240	1 in 9,700
South Asian	~43k	1 in 290	≈ 1 in 20,000
Remaining (unassigned)	~30k	1 in 210	≈ 1 in 9,900
European (Finnish)	~27k	1 in 340	1 in 3,200
Admixed American	~22k	1 in 110	1 in 3,700
African / African American	~21k	1 in 190	≈ 1 in 21,000
East Asian	~20k	1 in 280	none seen
Ashkenazi Jewish	~13k	1 in 620	none seen
Middle Eastern	~2,884	1 in 220	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 15 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 14 of 15 (exon 5 below).? see exons ↓