rs137852690 — STAR A218V

STAR missense variant abolishing steroidogenic activity; homozygous carriers develop lipoid congenital adrenal hyperplasia with absent cortisol, aldosterone, and sex hormone production

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STAR A218V — When the Steroid Hormone Switch Is Broken

Every steroid hormone your body makes — cortisol, aldosterone, testosterone, estrogen — begins with a single critical step: getting cholesterol from the cytoplasm into the inner mitochondrial membrane where the first enzyme of the steroid synthesis pathway lives. Steroidogenic Acute Regulatory protein (STAR)11 Steroidogenic Acute Regulatory protein (STAR)
Encoded by the STAR gene on chromosome 8; a 30 kDa protein rapidly induced by ACTH and LH to enable acute steroidogenesis is the gatekeeper of this transfer — without it, the entire steroidogenic cascade stalls regardless of how much cholesterol the cell has in reserve. The p.Ala218Val variant (c.653C>T, rs137852690) substitutes a valine for an alanine at position 218 of the STAR protein, located within the START cholesterol-binding domain, and eliminates steroidogenic activity entirely.

The Mechanism

The START domain of STAR forms a hydrophobic tunnel that binds a single cholesterol molecule and facilitates its transfer across the outer mitochondrial membrane. Alanine 218 sits within this cholesterol-binding pocket22 Alanine 218 sits within this cholesterol-binding pocket
The START (StAR-related lipid transfer) domain spans residues 63–285 of the mature STAR protein and is the evolutionarily conserved lipid-binding module, where it contributes to the precise geometry required for substrate binding. The substitution of valine (which has a bulkier branched side chain than alanine) disrupts critical residue interactions at the cholesterol- binding site, increasing local alpha-helix rigidity while reducing the protein's overall flexibility — changes that compromise cholesterol binding and release.

Transfection studies in COS-1 cells33 Transfection studies in COS-1 cells
A standard cell-based assay for steroidogenic activity using cells expressing P450scc/adrenodoxin alongside STAR constructs show that A218V produces zero steroidogenesis-enhancing activity — indistinguishable from an empty vector control. The protein is made but cannot perform its function. Arakane et al. further showed that A218V StAR is inactive not only in intact cells but also when added to isolated mitochondria44 Arakane et al. further showed that A218V StAR is inactive not only in intact cells but also when added to isolated mitochondria
Demonstrating that the defect is intrinsic to the protein, not a folding or targeting problem upstream, while simultaneously establishing that STAR acts on the outside of the outer mitochondrial membrane rather than needing to enter the organelle. Structural analysis confirms the mechanism: the A218V substitution produces incorrect protein folding55 Structural analysis confirms the mechanism: the A218V substitution produces incorrect protein folding
Bose et al. 1998: spectroscopic analysis of purified mutant StARs revealed that inactive mutants tend to form incorrect intermolecular beta-sheets rather than the predominantly alpha-helical structure of wild-type.

The Evidence

A218V is classified as pathogenic by ClinVar66 pathogenic by ClinVar
VCV000008993; 5 concordant submissions, 2-star review status (criteria provided, multiple submitters, no conflicts) for congenital lipoid adrenal hyperplasia (lipoid CAH; OMIM 201710). The condition disrupts the synthesis of all adrenal and gonadal steroid hormones simultaneously — cortisol, aldosterone, androgens, and estrogens are all produced through the same cholesterol-import step.

The clinical consequences depend on the specific genotype. Homozygous A218V carriers, or compound heterozygotes pairing A218V with a second loss-of-function STAR allele, develop classic lipoid CAH: severe adrenal crisis in the neonatal period or early infancy, with life-threatening salt-wasting (from absent aldosterone), hypoglycemia and cortisol deficiency, and complete sex reversal in 46,XY individuals (phenotypic females because no testicular testosterone was made during fetal development). Kim's 2014 review of the literature77 Kim's 2014 review of the literature
PMID 25654062 describes most cases presenting with "signs of severe adrenal failure in early infancy." Notably, 46,XX females with classic lipoid CAH can have spontaneous puberty because the ovary, unlike the adrenal gland, is relatively protected from cholesterol accumulation during fetal and early childhood life, preserving some function until puberty.

A218V was first characterized in a 1997 Japanese cohort study88 in a 1997 Japanese cohort study
Nakae et al., Human Molecular Genetics, PMID 9097960 alongside six other STAR mutations; all variants affecting the C-terminus showed no residual activity, explaining the severity of classic lipoid CAH. A more recent Iranian cohort study by Aghaei et al. 202399 Aghaei et al. 2023
PMID 37004560 reported A218V in twelve 46,XY patients presenting with male pseudohermaphroditism, providing the first structural explanation for its pathogenicity through molecular dynamics simulation.

Practical Implications

Heterozygous carriers of A218V have no symptoms — one functional STAR allele is sufficient for normal steroidogenesis. The relevance is entirely reproductive: carrier couples face a 25% chance per pregnancy of a homozygous or compound heterozygous child requiring lifelong hormone replacement from birth. Newborn screening programs in most countries do not routinely test for STAR variants; affected neonates present with salt-wasting adrenal crisis and can die before diagnosis if the underlying genetic cause is not recognized.

Individuals confirmed homozygous for A218V (or compound heterozygotes with a second null allele) require immediate endocrinology consultation. Management is lifelong: hydrocortisone and fludrocortisone replace adrenal hormones; sex steroid replacement is initiated at the expected age of puberty and tailored to the individual's gender identity; fertility is generally absent in 46,XY individuals but may be partially preserved in 46,XX individuals with mild forms of the disease.

Interactions

A218V is documented as a compound heterozygous pair with rs137852689 (STAR p.Arg217Thr)1010 rs137852689 (STAR p.Arg217Thr)
An adjacent missense variant also causing loss of StAR activity, reported in the same patient by Katsumata et al. 1999, where neither allele alone causes disease but both together eliminate steroidogenic function. This adjacent-residue compound heterozygosity illustrates that the region around position 217–218 of the START domain is critical to cholesterol-binding geometry. Clinically, A218V can also pair with any other STAR loss-of-function variant (splice site mutations, frameshift, nonsense alleles such as Q258X) to produce the same classic phenotype.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

Standard STAR function — cholesterol transport to mitochondria unaffected

You carry two copies of the common G allele at this position. Your STAR protein has the standard alanine at residue 218, with full cholesterol-transport activity and normal steroid hormone production through this pathway. This is by far the most common genotype — approximately 99.99% of people worldwide share it. You are not a carrier of this STAR variant and have no elevated risk of lipoid CAH from this specific position.

AG Carrier Carrier

Single copy of A218V — normal steroidogenesis, relevant for family planning

Lipoid congenital adrenal hyperplasia follows autosomal recessive inheritance: two copies of loss-of-function STAR alleles are required to produce disease. A single A218V allele paired with a wild-type allele produces no steroidogenic impairment; the unaffected copy provides ample STAR activity. This pattern is confirmed by the population frequency data — heterozygotes are essentially asymptomatic, while homozygotes or compound heterozygotes manifest severe adrenal and gonadal failure.

If your reproductive partner also carries a STAR pathogenic variant — A218V or any other null allele — each pregnancy carries a 25% chance of an affected child requiring lifelong hormone replacement therapy from the neonatal period. STAR carrier testing is available as a targeted variant test or as part of a comprehensive reproductive carrier screening panel.

AA Homozygous Homozygous

Two copies of A218V — STAR protein non-functional; lifelong steroid hormone replacement required

The A218V substitution within STAR's START domain destroys the protein's ability to transfer cholesterol across the outer mitochondrial membrane. Functional assays confirm zero steroidogenic activity — equivalent to having no STAR protein at all. Because every adrenal and gonadal steroid hormone (cortisol, aldosterone, DHEA, testosterone, estradiol, progesterone) requires this first cholesterol-import step, the entire steroidogenic cascade is blocked.

The clinical consequences are severe and sex-dependent: - Adrenal: absent cortisol and aldosterone from before birth. In the neonatal period, salt-wasting crisis (hyponatremia, hyperkalemia, hypotension), hypoglycemia, and circulatory collapse occur without replacement therapy. - Gonadal in 46,XY individuals: fetal testicular testosterone production is absent during the critical window for male genital differentiation, resulting in phenotypic female external genitalia (46,XY disorder of sex development / DSD). Gonads are streak-like and non-functional. These individuals are raised female and require estrogen replacement at puberty. - Gonadal in 46,XX individuals: ovarian function is relatively preserved in fetal life and early childhood (because folliculogenesis is not maximally active then), allowing spontaneous feminization at puberty. However, ovarian insufficiency progresses and fertility is typically impaired without hormonal support.

Cholesterol accumulates massively in adrenal cells because, unable to convert it, the gland continues to import it; this lipid engorgement gives the condition its name ("lipoid") and eventually destroys remaining adrenal cell architecture.

Diagnosis in an affected neonate requires immediate adrenal hormone replacement to prevent death. Long-term management is complex and requires paediatric endocrinology and, later, adult endocrinology expertise.