PRODH

Chr 22ADAR

proline dehydrogenase 1

Also known as: HSPOX2, PIG6, POX, PRODH1, TP53I6

NCBI Gene: 5625 ENSG00000100033 UniProt: O43272 OMIM: 606810

The protein converts proline to delta-1-pyrroline-5-carboxylate in the mitochondria as the first step of proline degradation. Mutations cause hyperprolinemia type I and confer susceptibility to schizophrenia, with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene is extremely tolerant to loss-of-function variants (pLI near zero) and is located in the 22q11.21 deletion syndrome region.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 1.102 OMIM phenotypes

Clinical Summary— PRODH

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Gene-Disease Validity (ClinGen)

hyperprolinemia type 1 · 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

26 unique Pathogenic / Likely Pathogenic· 192 VUS of 479 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PRODH

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.10LOEUF

pLI 0.000

Z-score 1.15

OE 0.76 (0.54–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.06Z-score

OE missense 0.99 (0.90–1.09)

307 obs / 310.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.54–1.10)

0≤0.351.4

Missense OE?0.99 (0.90–1.09)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 21 / 27.5Missense obs/exp: 307 / 310.2Syn Z: -0.79

This gene — mechanism propensity

0.7132th %ile

GOF

0.4973th %ile

LOF

0.2871th %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

479 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic9

VUS192

Likely Benign145

Benign83

Conflicting21

Pathogenic

Likely Pathogenic

192

VUS

145

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	1	6	0	17
Likely Pathogenic	6	2	1	0	9
VUS	6	158	23	5	192
Likely Benign	0	6	55	84	145
Benign	1	11	61	10	83
Conflicting	—				21
Total	23	178	146	99	467

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

View in ClinVar →

381 pathogenic / likely-pathogenic (of 453) ClinVar copy-number / structural variants overlap PRODH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →