OPLAH

Chr 8ADAR

5-oxoprolinase, ATP-hydrolysing

Also known as: 5-Opase, OPLA, OPLAHD

NCBI Gene: 26873 ENSG00000178814 UniProt: O14841 OMIM: 614243

The protein catalyzes the ATP-dependent cleavage of 5-oxo-L-proline to form L-glutamate as part of the gamma-glutamyl cycle. Mutations cause 5-oxoprolinase deficiency, which can be inherited in either autosomal dominant or autosomal recessive patterns. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene acts as a homodimer, using ATP hydrolysis to catalyze the conversion of 5-oxo-L-proline to L-glutamate. Defects in this gene are a cause of 5-oxoprolinase deficiency (OPLAHD). [provided by RefSeq, Jun 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.871 OMIM phenotype

Clinical Summary— OPLAH

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.33

OE 0.65 (0.49–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.27Z-score

OE missense 0.97 (0.92–1.03)

816 obs / 837.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.49–0.87)

0≤0.351.4

Missense OE?0.97 (0.92–1.03)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 34 / 52.2Missense obs/exp: 816 / 837.6Syn Z: -0.02

This gene — mechanism propensity

0.6745th %ile

GOF

0.7028th %ile

LOF

0.3357th %ile

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

GOFprediction above median

DNprediction 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.