DDHD2

Chr 8AR

DDHD domain containing 2

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

NCBI Gene: 23259 ENSG00000085788 UniProt: O94830 OMIM: 615003

The protein is a phospholipase enzyme that participates in membrane trafficking between the endoplasmic reticulum and Golgi body. Mutations cause autosomal recessive spastic paraplegia 54 through disruption of this intracellular membrane transport function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.771 OMIM phenotype

Clinical Summary— DDHD2

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

41 unique Pathogenic / Likely Pathogenic· 214 VUS of 448 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.77LOEUF

pLI 0.000

Z-score 2.76

OE 0.54 (0.39–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.07Z-score

OE missense 0.85 (0.77–0.93)

317 obs / 375.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.39–0.77)

0≤0.351.4

Missense OE?0.85 (0.77–0.93)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 23 / 42.4Missense obs/exp: 317 / 375.1Syn Z: 0.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDDHD2-related complex hereditary spastic paraplegiaLOFAR

This gene — mechanism propensity

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

0.6261th %ile

GOF

0.6247th %ile

LOF

0.2872th %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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

448 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic20

VUS214

Likely Benign135

Benign9

Conflicting14

Pathogenic

Likely Pathogenic

214

VUS

135

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	1	3	0	21
Likely Pathogenic	18	1	1	0	20
VUS	3	198	10	3	214
Likely Benign	0	11	60	64	135
Benign	0	2	7	0	9
Conflicting	—				14
Total	38	213	81	67	413

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

View in ClinVar →

60 pathogenic / likely-pathogenic (of 72) ClinVar copy-number / structural variants overlap DDHD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →