Is ABCG8 p.Ala449= (c.1347C>T) pathogenic?

ABCG8 p.Ala449= (c.1347C>T) is classified Likely benign in ABCG8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-25). Ultra-rare (popmax 0.0147%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Ala449= (c.1347C>T)?

ABCG8 p.Ala449= (c.1347C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCG8 p.Ala449= (c.1347C>T) in the general population?

ABCG8 p.Ala449= (c.1347C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

ABCG8 p.Ala449=

c.1347C>T · rs191130067 · VCV1770499

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

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 -7.1	GERP -3.1
Overall
CADD	0.272	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/75,008 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00496% 80/1,614,104 alleles · ultra-rare exomes 64/1,461,880 · genomes 16/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,819
South Asian	0.0121%	8,279
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)	0.00424%	23,601
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,006
East Asian	0.00223%	44,884

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.Ala449=
Coding: c.1347C>T
MANE Select: NM_022437
dbSNP: rs191130067
Type: single nucleotide variant
Location: chr2:43873922 (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 449: 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

Similar variants

ABCG8 p.Ala449Val Uncertain significance ★★ ⚠ same residue
ABCG8 p.Arg121Ter Pathogenic ★★ same condition
ABCG8 p.Arg405Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCG8 p.Gln271Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Ala248Thr Uncertain significance ★★ ⚠ same condition
ABCG8 p.Ala346Thr Uncertain significance ★★ ⚠ same condition
ABCG8 p.Ala450Thr Uncertain significance ★★ ⚠ same condition
ABCG8 p.Ala506Ser Uncertain significance ★★ ⚠ 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-ala449 (accessed [today's date]).

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