Is ABCG5 p.Val144Ala (c.431T>C) pathogenic?

ABCG5 p.Val144Ala (c.431T>C) is classified Uncertain significance in ABCG5 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-02). AlphaMissense: ambiguous (0.5121); Ultra-rare (popmax 0.0956%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ABCG5 p.Val144Ala (c.431T>C)?

ABCG5 p.Val144Ala (c.431T>C) is associated with Cardiovascular phenotype, sitosterolemia, sitosterolemia 2 (ClinVar).

How common is ABCG5 p.Val144Ala (c.431T>C) in the general population?

ABCG5 p.Val144Ala (c.431T>C) is ultra-rare (popmax 0.0956%, afr) (gnomAD).

What do computational predictors say about ABCG5 p.Val144Ala (c.431T>C)?

AlphaMissense predicts ambiguous (score 0.5121) — an in-silico prediction, not a clinical call.

ABCG5 p.Val144Ala

c.431T>C · rs376797531 · VCV197336

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.5121 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0956%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5121	ambiguous
REVEL	0.509	indeterminate
SaProt	LLR -12.05	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	26.2	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 0.0956% African / African-American · 71/74,304 alleles

Filtering AF 0.0777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0711%

Overall 0.00487% 77/1,582,268 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0956%	1,047
Remaining individualsnot grpmax-eligible	0.00489%	20,457
European (non-Finnish)	0.000257%	388,902

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.Val144Ala
Coding: c.431T>C
MANE Select: NM_022436
dbSNP: rs376797531
Type: single nucleotide variant
Location: chr2:43831839 (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 144: the abc transporter domain; an α-helix

Full ABCG5 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 sitosterolemia 2

Similar variants

ABCG5 p.Val144Met Uncertain significance ★ ⚠ same residue
ABCG5 p.Val144= Likely benign ★ same residue
ABCG5 c.1325-1G>T Likely pathogenic ★★ same condition
ABCG5 c.1464-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.634+1G>C Likely pathogenic ★★ same condition
ABCG5 c.904+1G>A Pathogenic ★★ same condition
ABCG5 p.Arg183Ter 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/abcg5-p-val144ala (accessed [today's date]).

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