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…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.43

LOEUF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in PYCR3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 88

412 rare PASS variants

Rare truncating (LoF)

1 in 1,700

78 rare PASS variants

Rare synonymous (reference)

1 in 190

212 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PYCR3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 2,100
South Asian	~43k	1 in 93	1 in 450
Remaining (unassigned)	~30k	1 in 73	1 in 1,100
European (Finnish)	~27k	1 in 740	1 in 2,400
Admixed American	~22k	1 in 73	1 in 1,600
African / African American	~21k	1 in 86	1 in 2,300
East Asian	~20k	1 in 75	1 in 1,100
Ashkenazi Jewish	~13k	1 in 340	≈ 1 in 4,100
Middle Eastern	~2,884	1 in 85	≈ 1 in 1,300

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓