PYCR1

Chr 17AR

pyrroline-5-carboxylate reductase 1

Also known as: ARCL2B, ARCL3B, P5C, P5CR, PIG45, PP222, PRO3, PYCR

NCBI Gene: 5831 ENSG00000183010 UniProt: P32322

This gene encodes an enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline. This enzyme may also play a physiologic role in the generation of NADP(+) in some cell types. The protein forms a homopolymer and localizes to the mitochondrion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Primary Disease Associations & Inheritance

Cutis laxa, autosomal recessive, type IIBMIM #612940

Cutis laxa, autosomal recessive, type IIIBMIM #614438

Active trials

Pathogenic / LP

402

ClinVar variants

Pubs (1 yr)

0.2

Missense Z

1.26

LOEUF

Clinical Summary— PYCR1

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Gene-Disease Validity (ClinGen)

autosomal recessive cutis laxa type 2B · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

68 Pathogenic / Likely Pathogenic· 139 VUS of 402 total submissions

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GeneReview available — PYCR1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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.

1.26LOEUF

pLI 0.000

Z-score 0.99

OE 0.67 (0.38–1.26)

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 0.97 (0.86–1.09)

187 obs / 193.8 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.0.67 (0.38–1.26)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.86–1.09)

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.0.98

0≤1.21.6

LoF obs/exp: 7 / 10.4Missense obs/exp: 187 / 193.8Syn Z: 0.17

0.7228th %ile

GOF

0.6052th %ile

LOF

0.3550th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.