AKR1D1

Chr 7AR

aldo-keto reductase family 1 member D1

Also known as: 3o5bred, CBAS2, SRD5B1

NCBI Gene: 6718ENSG00000122787UniProt: P51857

The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

Bile acid synthesis defect, congenital, 2MIM #235555
AR
UniProtCongenital bile acid synthesis defect 2
284
ClinVar variants
68
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— AKR1D1
🧬
Gene-Disease Validity (ClinGen)
congenital bile acid synthesis defect 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
68 Pathogenic / Likely Pathogenic· 136 VUS of 284 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.13LOEUF
pLI 0.000
Z-score 1.15
OE 0.71 (0.46–1.13)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.17Z-score
OE missense 0.96 (0.85–1.09)
175 obs / 181.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.71 (0.46–1.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.85–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11
0≤1.21.6
LoF obs/exp: 13 / 18.3Missense obs/exp: 175 / 181.5Syn Z: -0.66

ClinVar Variant Classifications

284 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic21
VUS136
Likely Benign31
Benign37
Conflicting12
47
Pathogenic
21
Likely Pathogenic
136
VUS
31
Likely Benign
37
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
45
0
47
Likely Pathogenic
11
5
5
0
21
VUS
0
67
63
6
136
Likely Benign
0
0
20
11
31
Benign
0
0
36
1
37
Conflicting
—12
Total127316918284

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

AKR1D1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

AKR1D1-related bile acid synthesis defect, congenital

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Bile acid synthesis defect, congenital, 2

MIM #235555

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — AKR1D1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease.
Nikolaou N et al.·Metabolism
2019
Recurrent AKR1D1 c.580-13T>A Variant: A Cause of Δ(4)-3-Oxosteroid-5β-Reductase Deficiency.
Zhao J et al.·J Mol Diagn
2023
Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis.
Guttman-Yassky E et al.·J Allergy Clin Immunol
2023
Infant cholestasis patient with a novel missense mutation in the AKR1D1 gene successfully treated by early adequate supplementation with chenodeoxycholic acid: A case report and review of the literature.
Wang HH et al.·World J Gastroenterol
2018Review
Clinical and genetic features of congenital bile acid synthesis defect with a novel mutation in AKR1D1 gene sequencing: Case reports.
Pham AN et al.·Medicine (Baltimore)
2022Case report
Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo.
Nikolaou N et al.·J Endocrinol
2020
Sudan II and IV induce liver carcinogenesis through interactions with AKR1D1 in computational and experimental studies insights from the Taiwan Sudan Red chili pepper incident.
Zhou L et al.·Ecotoxicol Environ Saf
2025
[Clinical feature and genetic analysis of a family affected by congenital bile acid synthesis defect type 2: identification of 2 novel mutations in AKR1D1 gene].
Cheng Y et al.·Zhongguo Dang Dai Er Ke Za Zhi
2017
The Mutational Landscape Of Genetic Cholestatic Diseases In Pakistani Children.
Cheema HA et al.·J Pak Med Assoc
2023
Ferroptosis induction, androgen biosynthesis disruption and prostate cancer suppression by androgen and vitamin D combination.
Park B et al.·Biochim Biophys Acta Gen Subj
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools