STARD5

Chr 15

StAR related lipid transfer domain containing 5

NCBI Gene: 80765 ENSG00000172345 UniProt: Q9NSY2

The protein functions as a cytosolic sterol transporter that moves cholesterol and related molecules between intracellular membranes, including from the cytoplasm to the endoplasmic reticulum and from the ER to the Golgi apparatus. STARD5 mutations cause autosomal recessive intellectual disability with seizures and spasticity, typically presenting in early childhood. The gene shows low constraint against loss-of-function variants (pLI = 0.00006), consistent with recessive inheritance where heterozygous carriers are unaffected.

ResearchSummary from RefSeq, UniProt

Proteins containing a steroidogenic acute regulatory-related lipid transfer (START) domain are often involved in the trafficking of lipids and cholesterol between diverse intracellular membranes. This gene is a member of the StarD subfamily that encodes START-related lipid transfer proteins. The protein encoded by this gene is a cholesterol transporter and is also able to bind and transport other sterol-derived molecules related to the cholesterol/bile acid biosynthetic pathways such as 25-hydroxycholesterol. Its expression is upregulated during endoplasmic reticulum (ER) stress. The protein is thought to act as a cytosolic sterol transporter that moves cholesterol between intracellular membranes such as from the cytoplasm to the ER and from the ER to the Golgi apparatus. Alternative splicing of this gene produces multiple transcript variants. [provided by RefSeq, Jan 2016]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.23

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.23LOEUF

pLI 0.000

Z-score 1.02

OE 0.68 (0.40–1.23)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.58Z-score

OE missense 0.85 (0.72–1.00)

100 obs / 117.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.40–1.23)

0≤0.351.4

Missense OE?0.85 (0.72–1.00)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 8 / 11.8Missense obs/exp: 100 / 117.8Syn Z: 0.32

Background carrier burden — how many people carry a rare variant somewhere in STARD5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

272 rare PASS variants

Rare truncating (LoF)

1 in 1,500

58 rare PASS variants

Rare synonymous (reference)

1 in 260

106 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for STARD5. 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 210	1 in 2,700
South Asian	~43k	1 in 130	1 in 600
Remaining (unassigned)	~30k	1 in 180	1 in 830
European (Finnish)	~27k	1 in 830	1 in 5,300
Admixed American	~22k	1 in 170	1 in 500
African / African American	~21k	1 in 180	1 in 1,200
East Asian	~20k	1 in 250	1 in 830
Ashkenazi Jewish	~13k	≈ 1 in 6,500	1 in 1,200
Middle Eastern	~2,884	1 in 200	≈ 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): 5 of 6 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 6.? see exons ↓