AKR1A1

Chr 1

aldo-keto reductase family 1 member A1

Also known as: ALDR1, ALR, ARM, DD3, HEL-S-6

NCBI Gene: 10327 ENSG00000117448 UniProt: P14550 OMIM: 103830

The protein functions as an aldehyde reductase that catalyzes NADPH-dependent reduction of aldehydes, ketones, and other carbonyl compounds, serving important roles in detoxification and cellular metabolism. Mutations cause autosomal recessive intellectual disability with facial dysmorphism and behavioral abnormalities. This gene is not highly constrained against loss-of-function variants based on population genetics data.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. This member, also known as aldehyde reductase, is involved in the reduction of biogenic and xenobiotic aldehydes and is present in virtually every tissue. Multiple alternatively spliced transcript variants of this gene exist, all encoding the same protein. [provided by RefSeq, Jan 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.12

Clinical Summary— AKR1A1

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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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ClinVar Variants

32 VUS of 49 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.12LOEUF

pLI 0.000

Z-score 1.19

OE 0.69 (0.44–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.02Z-score

OE missense 1.00 (0.89–1.13)

191 obs / 190.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.69 (0.44–1.12)

0≤0.351.4

Missense OE?1.00 (0.89–1.13)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 12 / 17.3Missense obs/exp: 191 / 190.2Syn Z: 0.53

This gene — mechanism propensity

0.6939th %ile

GOF

0.6639th %ile

LOF

0.2583th %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.

ClinVar Variant Classifications

49 submitted variants in ClinVar

ClinVar

Classification Summary

VUS32

Likely Benign2

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	32	0	0	32
Likely Benign	0	0	2	2
Benign	1	1	0	2
Total	33	1	2	36

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap AKR1A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →