AKR1C2

Chr 10AR

aldo-keto reductase family 1 member C2

Also known as: AKR1C-pseudo, BABP, DD, DD-2, DD/BABP, DD2, DDH2, HAKRD

NCBI Gene: 1646 ENSG00000151632 UniProt: P52895

This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme binds bile acid with high affinity, and shows minimal 3-alpha-hydroxysteroid dehydrogenase activity. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

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Primary Disease Associations & Inheritance

46XY sex reversal 8MIM #614279

UniProt46,XY sex reversal 8

Active trials

Pubs (1 yr)

P/LP submissions

—

P/LP missense

1.46

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— AKR1C2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.46LOEUF

pLI 0.000

Z-score 0.14

OE 0.96 (0.65–1.46)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-0.87Z-score

OE missense 1.20 (1.06–1.36)

176 obs / 146.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.96 (0.65–1.46)

0≤0.351.4

Missense OE1.20 (1.06–1.36)

0≤0.61.4

Synonymous OE1.31

0≤1.21.6

LoF obs/exp: 16 / 16.6Missense obs/exp: 176 / 146.3Syn Z: -1.87

0.76top 25%

GOF

0.6443th %ile

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.