Is ABCG5 p.Gln417Arg (c.1250A>G) pathogenic?

ABCG5 p.Gln417Arg (c.1250A>G) is classified Uncertain significance in ABCG5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-25). AlphaMissense: likely benign (0.2678); Ultra-rare (popmax 0.012%, afr); Associated with sitosterolemia 2.

What condition is associated with ABCG5 p.Gln417Arg (c.1250A>G)?

ABCG5 p.Gln417Arg (c.1250A>G) is associated with sitosterolemia 2 (ClinVar).

How common is ABCG5 p.Gln417Arg (c.1250A>G) in the general population?

ABCG5 p.Gln417Arg (c.1250A>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is Sitosterolemia inherited?

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

What do computational predictors say about ABCG5 p.Gln417Arg (c.1250A>G)?

AlphaMissense predicts likely benign (score 0.2678) — an in-silico prediction, not a clinical call.

ABCG5 p.Gln417Arg

c.1250A>G · rs1044958111 · VCV1760555

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sitosterolemia 2

Computational evidence

Protein change
AlphaMissense	0.2678	likely benign
REVEL	0.682	pathogenic-leaning
SaProt	LLR -9.48	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.5	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 0.012% African / African-American · 9/74,934 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000743% 12/1,614,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,326
Admixed American	0.00333%	29,999
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: ABCG5
Protein: p.Gln417Arg
Coding: c.1250A>G
MANE Select: NM_022436
dbSNP: rs1044958111
Type: single nucleotide variant
Location: chr2:43823987 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 8 PDB
Residue 417: the abc transmembrane type-2 domain; an α-helix

Full ABCG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

ABCG5 p.Gln417= Conflicting classifications of pathogenicity ★ same residue
ABCG5 c.1464-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg243Ter Pathogenic ★★ same condition
ABCG5 p.Arg389His Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCG5 p.Arg408Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg419His 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/abcg5-p-gln417arg (accessed [today's date]).

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