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…

Primary Disease Associations & Inheritance

Spastic paraplegia 54, autosomal recessiveMIM #615033

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Spastic paraplegia 54, autosomal recessive; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.77

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in DDHD2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 84

794 rare PASS variants

Rare truncating (LoF)

1 in 480

159 rare PASS variants

Rare synonymous (reference)

1 in 120

289 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DDHD2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 680
South Asian	~43k	1 in 100	1 in 630
Remaining (unassigned)	~30k	1 in 110	1 in 1,300
European (Finnish)	~27k	1 in 500	1 in 5,300
Admixed American	~22k	1 in 93	1 in 1,000
African / African American	~21k	1 in 70	1 in 630
East Asian	~20k	1 in 86	1 in 1,000
Ashkenazi Jewish	~13k	1 in 530	≈ 1 in 4,100
Middle Eastern	~2,884	1 in 120	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 11 of 16 coding exons well covered in gnomAD exomes; exons 4, 6, 9, 10, 11 marginal. Genomes: all 16.? see exons ↓