DDHD1

Chr 14AR

DDHD domain containing 1

Also known as: PA-PLA1, PAPLA1, SPG28, iPLA1I, iPLA1alpha

NCBI Gene: 80821 ENSG00000100523 UniProt: Q8NEL9 OMIM: 614603

The protein functions as an intracellular phospholipase A1 that preferentially hydrolyzes phosphatidic acid and regulates mitochondrial dynamics through its cytosolic and mitochondrial localization. Mutations cause autosomal recessive spastic paraplegia 28 (SPG28), characterized by progressive weakness and spasticity of the legs. The pathogenic mechanism involves loss of function leading to disrupted mitochondrial organization and dynamics.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the intracellular phospholipase A1 gene family. The protein encoded by this gene preferentially hydrolyzes phosphatidic acid. It is a cytosolic protein with some mitochondrial localization, and is thought to be involved in the regulation of mitochondrial dynamics. Overexpression of this gene causes fragmentation of the tubular structures in mitochondria, while depletion of the gene results in mitochondrial tubule elongation. Deletion of this gene in male mice caused fertility defects, resulting from disruption in the organization of the mitochondria during spermiogenesis. In humans, mutations in this gene have been associated with hereditary spastic paraplegia (HSP), also known as Strumpell-Lorrain disease, or, familial spastic paraparesis (FSP). This inherited disorder is characterized by progressive weakness and spasticity of the legs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.341 OMIM phenotype

Clinical Summary— DDHD1

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Gene-Disease Validity (ClinGen)

hereditary spastic paraplegia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.90). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

31 unique Pathogenic / Likely Pathogenic· 286 VUS of 592 total submissions

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GeneReview available — DDHD1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.902

Z-score 4.93

OE 0.19 (0.11–0.34)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.18Z-score

OE missense 0.85 (0.79–0.92)

427 obs / 501.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.11–0.34)

0≤0.351.4

Missense OE?0.85 (0.79–0.92)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 8 / 42.8Missense obs/exp: 427 / 501.4Syn Z: -0.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDDHD1-related spastic paraplegiaLOFAR

This gene — mechanism propensity

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

0.3694th %ile

GOF

0.4579th %ile

LOF

0.65top 25%

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.

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

ClinVar Variant Classifications

592 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25

Likely Pathogenic6

VUS286

Likely Benign201

Benign48

Conflicting12

Pathogenic

Likely Pathogenic

286

VUS

201

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	1	0	0	25
Likely Pathogenic	5	1	0	0	6
VUS	3	273	8	2	286
Likely Benign	0	10	77	114	201
Benign	0	5	38	5	48
Conflicting	—				12
Total	32	290	123	121	578

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap DDHD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →