SPR

Chr 2

sepiapterin reductase

Also known as: SDR38C1

NCBI Gene: 6697 ENSG00000116096 UniProt: P35270

The protein catalyzes the final reductions in tetrahydrobiopterin (BH4) biosynthesis through NADPH-dependent reduction of pteridine derivatives. Mutations cause dopa-responsive dystonia due to sepiapterin reductase deficiency, which can be inherited in either autosomal recessive or autosomal dominant patterns. The pathogenic mechanism involves deficient BH4 production, leading to impaired neurotransmitter synthesis.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes an aldo-keto reductase that catalyzes the NADPH-dependent reduction of pteridine derivatives and is important in the biosynthesis of tetrahydrobiopterin (BH4). Mutations in this gene result in DOPA-responsive dystonia due to sepiaterin reductase deficiency. A pseudogene has been identified on chromosome 1. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.14

Clinical Summary— SPR

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Gene-Disease Validity (ClinGen)

dopa-responsive dystonia due to sepiapterin reductase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

38 unique Pathogenic / Likely Pathogenic· 109 VUS of 282 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SPR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.14LOEUF

pLI 0.043

Z-score 1.35

OE 0.44 (0.20–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.73Z-score

OE missense 0.81 (0.69–0.96)

100 obs / 122.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.20–1.14)

0≤0.351.4

Missense OE?0.81 (0.69–0.96)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 3 / 6.8Missense obs/exp: 100 / 122.8Syn Z: 1.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPR-related DOPA-responsive dystonia due to sepiapterin reductase deficiencyLOFAR

This gene — mechanism propensity

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

0.7230th %ile

GOF

0.5563th %ile

LOF

0.2483th %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.

Literature Evidence

LOFThe findings indicate that haploinsufficiency of SPR can be a rare cause of DRD.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 15241655 ↗

ClinVar Variant Classifications

282 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic14

VUS109

Likely Benign114

Benign7

Conflicting14

Pathogenic

Likely Pathogenic

109

VUS

114

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	5	3	0	24
Likely Pathogenic	10	4	0	0	14
VUS	1	91	16	1	109
Likely Benign	0	0	21	93	114
Benign	0	0	6	1	7
Conflicting	—				14
Total	27	100	46	95	282

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap SPR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →