CYP11A1

Chr 15

cytochrome P450 family 11 subfamily A member 1

ENSG00000140459 UniProt: P05108 OMIM: 118485

This cytochrome P450 enzyme catalyzes the conversion of cholesterol to pregnenolone in the mitochondrial inner membrane, representing the first and rate-limiting step in steroid hormone synthesis. Mutations cause congenital adrenal insufficiency with partial or complete 46XY sex reversal, inherited in an autosomal recessive pattern. The gene shows low constraint against loss-of-function variants (LOEUF 0.881), and affected individuals present with severe adrenal insufficiency and disorders of sex development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

A cytochrome P450 monooxygenase that catalyzes the side-chain hydroxylation and cleavage of cholesterol to pregnenolone, the precursor of most steroid hormones (PubMed:21636783). Catalyzes three sequential oxidation reactions of cholesterol, namely the hydroxylation at C22 followed with the hydroxylation at C20 to yield 20R,22R-hydroxycholesterol that is further cleaved between C20 and C22 to yield the C21-steroid pregnenolone and 4-methylpentanal (PubMed:21636783). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:21636783)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Adrenal insufficiency, congenital, with 46XY sex reversal, partial or completeMIM #613743

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete; no ClinGen or GenCC tier

Active trials

321

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.88

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.000

Z-score 2.01

OE 0.56 (0.37–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.77Z-score

OE missense 0.88 (0.80–0.97)

277 obs / 315.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.37–0.88)

0≤0.351.4

Missense OE?0.88 (0.80–0.97)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 14 / 24.8Missense obs/exp: 277 / 315.4Syn Z: 0.63

Background carrier burden — how many people carry a rare variant somewhere in CYP11A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

645 rare PASS variants

Rare truncating (LoF)

1 in 2,300

73 rare PASS variants

Rare synonymous (reference)

1 in 160

260 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CYP11A1. 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 120	1 in 2,000
South Asian	~43k	1 in 98	1 in 2,400
Remaining (unassigned)	~30k	1 in 95	1 in 6,000
European (Finnish)	~27k	1 in 220	≈ 1 in 13,000
Admixed American	~22k	1 in 87	1 in 2,000
African / African American	~21k	1 in 63	≈ 1 in 6,000
East Asian	~20k	1 in 85	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 220	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 84	≈ 1 in 2,900

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): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓