PYCR3

Chr 8

pyrroline-5-carboxylate reductase 3

Also known as: PYCRL

NCBI Gene: 65263ENSG00000104524UniProt: Q53H96OMIM: 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.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 1.43
Clinical Summary— PYCR3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
14 unique Pathogenic / Likely Pathogenic· 69 VUS of 100 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 OE0.79 (0.47–1.43)
0≤0.351.4
Missense OE1.00 (0.88–1.13)
0≤0.61.4
Synonymous OE1.21
0≤1.21.6
LoF obs/exp: 8 / 10.1Missense obs/exp: 172 / 172.2Syn Z: -1.47
DN
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

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic1
VUS69
Likely Benign3
13
Pathogenic
1
Likely Pathogenic
69
VUS
3
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
13
0
13
Likely Pathogenic
0
0
1
0
1
VUS
0
61
8
0
69
Likely Benign
0
2
0
1
3
Benign
0
0
0
0
0
Total06322186

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

View in ClinVar →

Protein Context — Lollipop Plot

PYCR3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC

No open access results found

Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients