PTDSS1

Chr 8AD

phosphatidylserine synthase 1

Also known as: LMHD, PSS1, PSSA

NCBI Gene: 9791 ENSG00000156471 UniProt: P48651 OMIM: 612792

This enzyme catalyzes the formation of phosphatidylserine from phosphatidylcholine or phosphatidylethanolamine through a base-exchange reaction, producing a critical membrane phospholipid involved in cellular structure and signaling. Mutations cause Lenz-Majewski hyperostotic dwarfism, a rare disorder characterized by skeletal abnormalities and overgrowth, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.448), indicating it is intolerant to complete protein loss.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene catalyzes the formation of phosphatidylserine from either phosphatidylcholine or phosphatidylethanolamine. Phosphatidylserine localizes to the mitochondria-associated membrane of the endoplasmic reticulum, where it serves a structural role as well as a signaling role. Defects in this gene are a cause of Lenz-Majewski hyperostotic dwarfism. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Lenz-Majewski hyperostotic dwarfismMIM #151050

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Lenz-Majewski hyperostotic dwarfism; no ClinGen or GenCC tier

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.45

LOEUF

GOF

Mechanism· G2P

📖

GeneReview available — PTDSS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.151

Z-score 3.95

OE 0.25 (0.14–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.38Z-score

OE missense 0.59 (0.52–0.67)

158 obs / 267.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.14–0.45)

0≤0.351.4

Missense OE?0.59 (0.52–0.67)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 8 / 32.2Missense obs/exp: 158 / 267.4Syn Z: 0.47

Background carrier burden — how many people carry a rare variant somewhere in PTDSS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

509 rare PASS variants

Rare truncating (LoF)

1 in 1,900

89 rare PASS variants

Rare synonymous (reference)

1 in 210

220 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PTDSS1. 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 200	1 in 2,000
South Asian	~43k	1 in 150	1 in 3,200
Remaining (unassigned)	~30k	1 in 140	1 in 3,000
European (Finnish)	~27k	1 in 920	≈ 1 in 6,700
Admixed American	~22k	1 in 210	1 in 1,600
African / African American	~21k	1 in 120	1 in 1,800
East Asian	~20k	1 in 150	1 in 1,600
Ashkenazi Jewish	~13k	1 in 590	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 180	none seen

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): All 13 coding exons well covered in gnomAD exomes and genomes.? see exons ↓