Is STAR p.Arg53Pro (c.158G>C) pathogenic?

STAR p.Arg53Pro (c.158G>C) is classified Uncertain significance in STAR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-23). AlphaMissense: ambiguous (0.4101); Very rare (popmax 0.00267%, afr); Associated with congenital lipoid adrenal hyperplasia due to STAR deficency.

What condition is associated with STAR p.Arg53Pro (c.158G>C)?

STAR p.Arg53Pro (c.158G>C) is associated with congenital lipoid adrenal hyperplasia due to STAR deficency (ClinVar).

How common is STAR p.Arg53Pro (c.158G>C) in the general population?

STAR p.Arg53Pro (c.158G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about STAR p.Arg53Pro (c.158G>C)?

AlphaMissense predicts ambiguous (score 0.4101) — an in-silico prediction, not a clinical call.

STAR p.Arg53Pro

Q: How is Congenital lipoid adrenal hyperplasia due to STAR deficency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.158G>C · rs529036391 · VCV911472

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

congenital lipoid adrenal hyperplasia due to STAR deficency

Computational evidence

Protein change
AlphaMissense	0.4101	ambiguous
REVEL	0.316	indeterminate
SaProt	LLR -7.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.099	GERP 0.38
Regional constraint	o/e 0.99	unconstrained · MANE · 6,542 bp · p 0.84 · regional, not allelic
Overall
CADD	18.11	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,952 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00136% 22/1,614,034 alleles · very rare exomes 20/1,461,790 · genomes 2/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,476
Remaining individualsnot grpmax-eligible	0.0016%	62,482
Finnishnot grpmax-eligible	0.00156%	63,954
European (non-Finnish)	0.00153%	65,558

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: STAR
Protein: p.Arg53Pro
Coding: c.158G>C
MANE Select: NM_000349
dbSNP: rs529036391
Type: single nucleotide variant
Location: chr8:38148661 (GRCh38)
Gene constraint: LOEUF 1.297 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.71 · 4 PDB

Full STAR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital lipoid adrenal hyperplasia due to STAR deficency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital lipoid adrenal hyperplasia due to STAR deficency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

STAR p.Arg53Gly Uncertain significance ★★ ⚠ same residue
STAR p.Arg53Leu Likely benign ★★ same residue
STAR p.Arg53Gln Uncertain significance ★ ⚠ same residue
STAR p.Arg53= Likely benign ★ same residue
STAR c.178+1G>C Likely pathogenic ★★ same condition
STAR c.306+1G>A Likely pathogenic ★★ same condition
STAR c.307-1G>C Likely pathogenic ★★ same condition
STAR c.465+2T>C Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/star-p-arg53pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown