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 OMIM: 179035

This mitochondrial enzyme catalyzes the final step in proline biosynthesis by reducing pyrroline-5-carboxylate to L-proline using NAD(P)H and is involved in cellular oxidative stress responses. Mutations cause autosomal recessive cutis laxa types IIB and IIIB, connective tissue disorders characterized by loose, sagging skin and other systemic features. The gene shows tolerance to loss-of-function variants (low pLI score), consistent with the recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.262 OMIM phenotypes

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

47 unique Pathogenic / Likely Pathogenic· 134 VUS of 378 total submissions

Explore recent and relevant literature in Research Assistant →

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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?

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?

0.17Z-score

OE missense 0.97 (0.86–1.09)

187 obs / 193.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.38–1.26)

0≤0.351.4

Missense OE?0.97 (0.86–1.09)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePYCR1-related cutis laxaLOFAR

strongPYCR1-related cutis laxa (de Barsy syndrome)OTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7228th %ile

GOF

0.6052th %ile

LOF

0.3550th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

378 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic28

VUS134

Likely Benign155

Benign16

Conflicting23

Pathogenic

Likely Pathogenic

134

VUS

155

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	4	0	0	19
Likely Pathogenic	18	10	0	0	28
VUS	3	108	23	0	134
Likely Benign	0	6	71	78	155
Benign	0	3	10	3	16
Conflicting	—				23
Total	36	131	104	81	375

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap PYCR1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →