Is ABCG8 p.Val378Met (c.1132G>A) pathogenic?

ABCG8 p.Val378Met (c.1132G>A) is classified Uncertain significance in ABCG8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-29). AlphaMissense: likely benign (0.0775); Very rare (popmax 0.00439%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Val378Met (c.1132G>A)?

ABCG8 p.Val378Met (c.1132G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCG8 p.Val378Met (c.1132G>A) in the general population?

ABCG8 p.Val378Met (c.1132G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ABCG8 p.Val378Met (c.1132G>A)?

AlphaMissense predicts likely benign (score 0.0775) — an in-silico prediction, not a clinical call.

ABCG8 p.Val378Met

c.1132G>A · rs562447483 · VCV1728848

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0775 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0775	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37	GERP -0.5, phastCons 0.006
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	12.31	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,070 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00143% 23/1,613,848 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,767
Admixed American	0.00167%	60,002
European (non-Finnish)	0.00144%	69,413
African / African-American	0.00134%	74,892

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.Val378Met
Coding: c.1132G>A
MANE Select: NM_022437
dbSNP: rs562447483
Type: single nucleotide variant
Location: chr2:43872227 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 8 PDB

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-val378met (accessed [today's date]).

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