Is ABCG8 p.Arg220fs (c.647_657dup) pathogenic?

ABCG8 p.Arg220fs (c.647657dup) is classified Pathogenic/Likely pathogenic in ABCG8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-29). Rare (popmax 0.108%, amr); Associated with ABCG8-related disorder.

What condition is associated with ABCG8 p.Arg220fs (c.647_657dup)?

ABCG8 p.Arg220fs (c.647_657dup) is associated with ABCG8-related disorder, sitosterolemia, sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Arg220fs (c.647_657dup) in the general population?

ABCG8 p.Arg220fs (c.647_657dup) is rare (popmax 0.108%, amr) (gnomAD).

ABCG8 p.Arg220fs

c.647_657dup · rs1456237152 · VCV501952

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.108%, amr)

Conditions

ABCG8-related disorder

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 5 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 1.1, phastCons 1
Overall
CADD	33.0	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 0.108% Admixed American · 65/59,990 alleles

Filtering AF 0.0872% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0795%

Overall 0.00415% 67/1,612,826 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.108%	923
Remaining individualsnot grpmax-eligible	0.00321%	31,191

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.Arg220fs
Coding: c.647_657dup
MANE Select: NM_022437
dbSNP: rs1456237152
Type: Duplication
Location: chr2:43852436 (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 220: the abc transporter domain; an α-helix

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

Disease context

ABCG8-related disorder

Also linked: sitosterolemia sitosterolemia 1

Similar variants

ABCG8 p.Lys94delinsMetTer Likely pathogenic ★ same condition
ABCG8 p.Val539fs Pathogenic same condition
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.Gln137fs 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-arg220fs (accessed [today's date]).

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