Is ABCG8 p.Ala149Val (c.446C>T) pathogenic?

ABCG8 p.Ala149Val (c.446C>T) is classified Uncertain significance in ABCG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-24). AlphaMissense: ambiguous (0.5218); Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Ala149Val (c.446C>T)?

ABCG8 p.Ala149Val (c.446C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCG8 p.Ala149Val (c.446C>T) in the general population?

ABCG8 p.Ala149Val (c.446C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ABCG8 p.Ala149Val (c.446C>T)?

AlphaMissense predicts ambiguous (score 0.5218) — an in-silico prediction, not a clinical call.

ABCG8 p.Ala149Val

c.446C>T · rs748508780 · VCV3227789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5218	ambiguous
REVEL	0.485	indeterminate
SaProt	LLR -9.40	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	27.9	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 0.0011% South Asian · 1/91,088 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000805% 13/1,614,096 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,088
European (non-Finnish)	0.00102%	98,337

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.Ala149Val
Coding: c.446C>T
MANE Select: NM_022437
dbSNP: rs748508780
Type: single nucleotide variant
Location: chr2:43851707 (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 149: the abc transporter domain; a β-strand

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.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.Ala449Val 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-ala149val (accessed [today's date]).

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