HPDL

Chr 1

4-hydroxyphenylpyruvate dioxygenase like

Also known as: 4-HPPD-L, GLOXD1, NEDSWMA, SPG83

NCBI Gene: 84842 ENSG00000186603 UniProt: Q96IR7

The protein is an iron-dependent mitochondrial dioxygenase that catalyzes the conversion of 4-hydroxyphenylpyruvate to 4-hydroxymandelate in coenzyme Q10 biosynthesis from tyrosine. Biallelic mutations cause autosomal recessive pediatric-onset spastic movement disorder with neurodevelopmental features and brain white matter abnormalities, also known as spastic paraplegia 83. The gene shows low constraint against loss-of-function variants (pLI near 0), consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this intronless gene localizes to mitochondria, where it may function as 4-hydroxyphenylpyruvate dioxygenase. Clinical studies have identified several bi-allelic variants in this gene that lower the level of the encoded protein and lead to a clinically variable form of pediatric-onset spastic movement disorder. [provided by RefSeq, Aug 2020]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.43

Clinical Summary— HPDL

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

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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

52 unique Pathogenic / Likely Pathogenic· 59 VUS of 128 total submissions

Explore recent and relevant literature in Research Assistant →

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?

1.43LOEUF

pLI 0.000

Z-score 0.59

OE 0.80 (0.47–1.43)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.93Z-score

OE missense 0.83 (0.74–0.93)

197 obs / 237.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.80 (0.47–1.43)

0≤0.351.4

Missense OE?0.83 (0.74–0.93)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 8 / 10.0Missense obs/exp: 197 / 237.5Syn Z: 1.21

ClinVar Variant Classifications

128 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic35

VUS59

Likely Benign10

Benign3

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	6	3	0	17
Likely Pathogenic	17	18	0	0	35
VUS	1	58	0	0	59
Likely Benign	0	7	0	3	10
Benign	0	0	1	2	3
Conflicting	—				4
Total	26	89	4	5	128

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap HPDL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →