Is ABCG8 p.Pro523= (c.1569A>G) pathogenic?

ABCG8 p.Pro523= (c.1569A>G) is classified Conflicting classifications of pathogenicity in ABCG8 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-31). Rare (popmax 0.452%, sas); Associated with sitosterolemia 1.

What condition is associated with ABCG8 p.Pro523= (c.1569A>G)?

ABCG8 p.Pro523= (c.1569A>G) is associated with sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Pro523= (c.1569A>G) in the general population?

ABCG8 p.Pro523= (c.1569A>G) is rare (popmax 0.452%, sas) (gnomAD).

How is Sitosterolemia inherited?

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

ABCG8 p.Pro523=

c.1569A>G · rs575386215 · VCV336085

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.452%, sas)

Conditions

sitosterolemia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -2.9
Overall
CADD	0.021	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.452% South Asian · 412/91,086 alleles

Filtering AF 0.416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.402%

Overall 0.0269% 435/1,614,220 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.452%	221
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0256%	3,907
East Asian	0.00223%	44,888
Admixed American	0.00167%	60,034
European (non-Finnish)	0.000169%	590,023

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: ABCG8
Protein: p.Pro523=
Coding: c.1569A>G
MANE Select: NM_022437
dbSNP: rs575386215
Type: single nucleotide variant
Location: chr2:43875226 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 8 PDB
Residue 523: the abc transmembrane type-2 domain

Full ABCG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

ABCG8 p.Pro523Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCG8 p.Pro523Ala Uncertain significance ★ ⚠ same residue
ABCG8 c.64-2A>G Pathogenic ★★ same condition
ABCG8 c.965-1G>C Pathogenic ★★ same condition
ABCG8 p.Arg164Ter Pathogenic ★★ same condition
ABCG8 p.Arg405Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCG8 p.Arg412Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Gly574Arg 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/abcg8-p-pro523 (accessed [today's date]).

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