PYCR3

Chr 8

pyrroline-5-carboxylate reductase 3

Also known as: PYCRL

NCBI Gene: 65263 ENSG00000104524 UniProt: Q53H96 OMIM: 616408

The protein catalyzes the final step in proline biosynthesis, reducing pyrroline-5-carboxylate to proline using NADH/NADPH, and is specifically involved in the ornithine-to-proline biosynthetic pathway. Biallelic mutations cause autosomal recessive hypomyelinating leukodystrophy-10, presenting in infancy with severe developmental delays, hypotonia, seizures, and progressive brain atrophy. The gene shows low constraint to loss-of-function variation, consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that belongs to the pyrroline-5-carboxylate reductase family of enzymes. Members of this family catalyze the final step in proline biosynthesis, converting pyrroline-5-carboxylate to proline. Glutamate and ornithine are precursors in the synthesis of proline. The protein encoded by this gene is a cytoplasmic enzyme involved in the biosynthesis of proline from ornithine. [provided by RefSeq, Aug 2016]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.43

Clinical Summary— PYCR3

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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

66 VUS of 83 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.43LOEUF

pLI 0.000

Z-score 0.61

OE 0.79 (0.47–1.43)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.01Z-score

OE missense 1.00 (0.88–1.13)

172 obs / 172.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.79 (0.47–1.43)

0≤0.351.4

Missense OE?1.00 (0.88–1.13)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 8 / 10.1Missense obs/exp: 172 / 172.2Syn Z: -1.47

This gene — mechanism propensity

0.76top 25%

GOF

0.6052th %ile

LOF

0.3068th %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.

ClinVar Variant Classifications

83 submitted variants in ClinVar

ClinVar

Classification Summary

VUS66

Likely Benign3

VUS

Likely 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	62	4	0	66
Likely Benign	2	0	1	3
Benign	0	0	0	0
Total	64	4	1	69

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

View in ClinVar →

60 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap PYCR3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →