DDHD2

Chr 8AR

DDHD domain containing 2

Also known as: SAMWD1, SPG54, iPLA(1)gamma, iPLA1A, iPLA1gamma, p125B

NCBI Gene: 23259ENSG00000085788UniProt: O94830

This gene encodes a phospholipase enzyme containing sterile-alpha-motif (SAM), WWE, and DDHD domains. This protein participates in membrane trafficking between the endoplastic reticulum and the Golgi body. Mutations in this gene can cause autosomal recessive spastic paraplegia 54. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

Primary Disease Associations & Inheritance

Spastic paraplegia 54, autosomal recessiveMIM #615033
AR
481
ClinVar variants
100
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— DDHD2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
100 Pathogenic / Likely Pathogenic· 225 VUS of 481 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.77LOEUF
pLI 0.000
Z-score 2.76
OE 0.54 (0.39–0.77)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.07Z-score
OE missense 0.85 (0.77–0.93)
317 obs / 375.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.54 (0.39–0.77)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.77–0.93)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 23 / 42.4Missense obs/exp: 317 / 375.1Syn Z: 0.42

ClinVar Variant Classifications

481 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic79
Likely Pathogenic21
VUS225
Likely Benign134
Benign9
Conflicting13
79
Pathogenic
21
Likely Pathogenic
225
VUS
134
Likely Benign
9
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
1
70
0
79
Likely Pathogenic
8
1
12
0
21
VUS
3
194
25
3
225
Likely Benign
0
11
60
63
134
Benign
0
2
7
0
9
Conflicting
—13
Total1920917466481

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

View in ClinVar →

Protein Context — Lollipop Plot

DDHD2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

DDHD2-related complex hereditary spastic paraplegia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spastic paraplegia 54, autosomal recessive

MIM #615033

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Biallelic DDHD2 mutations in patients with adult-onset complex hereditary spastic paraplegia.
Chou YT et al.·Ann Clin Transl Neurol
2023Cohort
Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis.
Guo LK et al.·Mil Med Res
2023
Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism.
Matoba N et al.·Transl Psychiatry
2020Meta-analysis
Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke.
Zhao X et al.·BMC Neurol
2025
Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis.
Maruyama T et al.·Cell Death Dis
2018
Defining the clinical-genetic and neuroradiological features in SPG54: description of eight additional cases and nine novel DDHD2 variants.
Nicita F et al.·J Neurol
2019Cohort
Palmitoylation Dynamics in Systemic Lupus Erythematosus: Multi-Omics Insights and Potential Therapeutic Implications.
Liu Z et al.·Int J Rheum Dis
2025
Pan-cancer analysis of the oncogenic role of ZNF703 in regulating tumor immunity.
Shi X et al.·BMC Cancer
2025
Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis.
Citterio A et al.·J Neurol
2014
Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5.
Sun L et al.·Front Med
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools