Is ABCG8 p.Leu451= (c.1353C>T) pathogenic?

ABCG8 p.Leu451= (c.1353C>T) is classified Conflicting classifications of pathogenicity in ABCG8 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-03-10). Very rare (popmax 0.00669%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Leu451= (c.1353C>T)?

ABCG8 p.Leu451= (c.1353C>T) is associated with Cardiovascular phenotype, sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Leu451= (c.1353C>T) in the general population?

ABCG8 p.Leu451= (c.1353C>T) is very rare (popmax 0.00669%, nfe) (gnomAD).

ABCG8 p.Leu451=

c.1353C>T · rs373560827 · VCV594738

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, nfe)

Conditions

Cardiovascular phenotype

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 -0.51	GERP -3.1
Overall
CADD	2.342	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% European (non-Finnish) · 79/1,180,054 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00502% 81/1,614,074 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00669%	14,937
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,922

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.Leu451=
Coding: c.1353C>T
MANE Select: NM_022437
dbSNP: rs373560827
Type: single nucleotide variant
Location: chr2:43873928 (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 451: the abc transmembrane type-2 domain; an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sitosterolemia 1

Similar variants

ABCG8 p.Leu451Phe Uncertain significance ★ ⚠ same residue
ABCG8 p.Leu451Val Uncertain significance ★ ⚠ same residue
ABCG8 c.64-2A>G Pathogenic ★★ same condition
ABCG8 c.965-1G>C Pathogenic ★★ same condition
ABCG8 p.Arg121Ter 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

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-leu451 (accessed [today's date]).

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