Is ABCG5 p.Arg419Pro (c.1256G>C) pathogenic?

ABCG5 p.Arg419Pro (c.1256G>C) is classified Pathogenic in ABCG5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2001-01-01). AlphaMissense: likely pathogenic (0.9816); Very rare (popmax 8.47e-05%, nfe); Associated with sitosterolemia 2.

What condition is associated with ABCG5 p.Arg419Pro (c.1256G>C)?

ABCG5 p.Arg419Pro (c.1256G>C) is associated with sitosterolemia 2 (ClinVar).

How common is ABCG5 p.Arg419Pro (c.1256G>C) in the general population?

ABCG5 p.Arg419Pro (c.1256G>C) is very rare (popmax 8.47e-05%, nfe) (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.Arg419Pro (c.1256G>C)?

AlphaMissense predicts likely pathogenic (score 0.9816) — an in-silico prediction, not a clinical call.

ABCG5 p.Arg419Pro

c.1256G>C · rs119479067 · VCV4979

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9816 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sitosterolemia 2

Computational evidence

Protein change
AlphaMissense	0.9816	likely pathogenic ✓ concordant with ClinVar · top 1% in ABCG5
REVEL	0.702	pathogenic-leaning
SaProt	LLR -12.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	25.0	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 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 0.000657% 1/152,170 alleles · very rare

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.Arg419Pro
Coding: c.1256G>C
MANE Select: NM_022436
dbSNP: rs119479067
Type: single nucleotide variant
Location: chr2:43823981 (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 419: the abc transmembrane type-2 domain; a UniProt-annotated variant site (in stsl2; loss of normal maturation of glycan chains); a UniProt-annotated variant site (in stsl2; strongly decreased maturation of glycan chains); 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.Arg419His Pathogenic ★★ ⚠ same residue
ABCG5 p.Arg419Cys Uncertain significance ★★ ⚠ same residue
ABCG5 p.Arg419Gly Uncertain significance ★ ⚠ same residue
ABCG5 p.Arg419= Likely benign ★ 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

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-arg419pro (accessed [today's date]).

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