STARD5

Chr 15

StAR related lipid transfer domain containing 5

NCBI Gene: 80765 ENSG00000172345 UniProt: Q9NSY2 OMIM: 607050

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.23

Clinical Summary— STARD5

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Population Constraint (gnomAD)

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

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ClinVar Variants

32 VUS of 44 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?

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

This gene — mechanism propensity

0.6840th %ile

GOF

0.73top 25%

LOF

0.2092th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

44 submitted variants in ClinVar

ClinVar

Classification Summary

VUS32

Likely Benign2

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	32	0	32
Likely Benign	2	0	2
Benign	0	1	1
Total	34	1	35

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap STARD5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →