Is ABCG8 p.Val225= (c.675G>A) pathogenic?

ABCG8 p.Val225= (c.675G>A) is classified Benign/Likely benign in ABCG8 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 12%, mid) — too common for a highly-penetrant pathogenic allele; Associated with sitosterolemia 1.

What condition is associated with ABCG8 p.Val225= (c.675G>A)?

ABCG8 p.Val225= (c.675G>A) is associated with sitosterolemia 1 (ClinVar).

How is Sitosterolemia inherited?

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

ABCG8 p.Val225=

Q: How common is ABCG8 p.Val225= (c.675G>A) in the general population?

ABCG8 p.Val225= (c.675G>A) is common (popmax 12%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.675G>A · rs9282575 · VCV336072

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 12%, mid) — too common for a highly-penetrant pathogenic allele

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 1.2	GERP -2.8, phastCons 1
Overall
CADD	6.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12% Middle Eastern · 668/5,548 alleles

Filtering AF 11.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 11%

Overall 4.97% 80,188/1,613,262 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	12%	8
South Asian	10.5%	10
Ashkenazi Jewishnot grpmax-eligible	7.5%	13
African / African-American	6.15%	16
Remaining individualsnot grpmax-eligible	5.38%	19
European (non-Finnish)	4.81%	21
Amishnot grpmax-eligible	3.62%	28
Admixed American	3.09%	32
Finnishnot grpmax-eligible	1.85%	54
East Asian	0.0178%	5,608

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.Val225=
Coding: c.675G>A
MANE Select: NM_022437
dbSNP: rs9282575
Type: single nucleotide variant
Location: chr2:43852467 (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 225: the abc transporter domain; an α-helix

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.Val225Glu 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
ABCG8 p.Ser107Ter 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-val225 (accessed [today's date]).

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