Is STAR p.Ser46fs (c.135del) pathogenic?

STAR p.Ser46fs (c.135del) is classified Pathogenic/Likely pathogenic in STAR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-01-23). Very rare (popmax 0.00768%, sas); Associated with congenital lipoid adrenal hyperplasia due to STAR deficency.

What condition is associated with STAR p.Ser46fs (c.135del)?

STAR p.Ser46fs (c.135del) is associated with congenital lipoid adrenal hyperplasia due to STAR deficency (ClinVar).

How common is STAR p.Ser46fs (c.135del) in the general population?

STAR p.Ser46fs (c.135del) is very rare (popmax 0.00768%, sas) (gnomAD).

STAR p.Ser46fs

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.135del · rs193922393 · VCV36782

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00768%, sas)

Conditions

congenital lipoid adrenal hyperplasia due to STAR deficency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.34	GERP -4.4
Overall
CADD	3.541	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00768% South Asian · 7/91,096 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000805% 13/1,614,004 alleles · very rare exomes 12/1,461,790 · genomes 1/152,214 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00768%	13,014
European (non-Finnish)	0.000508%	196,674

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.Ser46fs
Coding: c.135del
MANE Select: NM_000349
dbSNP: rs193922393
Type: Deletion
Location: chr8:38148684 (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.Ser46Gly Uncertain significance ★ ⚠ same residue
STAR p.Glu136fs Pathogenic ★★ same condition
STAR p.Gly232fs Pathogenic ★★ same condition
STAR p.Leu271fs Pathogenic/Likely pathogenic ★★ same condition
STAR p.Lys238fs Pathogenic ★★ same condition
STAR p.Thr240fs Pathogenic ★★ same condition
STAR p.Val226fs Pathogenic/Likely pathogenic ★★ same condition
STAR c.745-1_757del 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-ser46fs (accessed [today's date]).

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