Is ABCG5 p.Val76Met (c.226G>A) pathogenic?

ABCG5 p.Val76Met (c.226G>A) is classified Uncertain significance in ABCG5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-04). AlphaMissense: likely benign (0.1021); Ultra-rare (popmax 0.024%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ABCG5 p.Val76Met (c.226G>A)?

ABCG5 p.Val76Met (c.226G>A) is associated with Cardiovascular phenotype, sitosterolemia (ClinVar).

How common is ABCG5 p.Val76Met (c.226G>A) in the general population?

ABCG5 p.Val76Met (c.226G>A) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about ABCG5 p.Val76Met (c.226G>A)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

ABCG5 p.Val76Met

c.226G>A · rs368811625 · VCV857096

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.393	indeterminate
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.1	GERP -3.2
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	4.8	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 0.024% African / African-American · 18/74,934 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00223% 36/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,163
Admixed American	0.005%	20,003
East Asian	0.00223%	44,882
South Asian	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000932%	107,272

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.Val76Met
Coding: c.226G>A
MANE Select: NM_022436
dbSNP: rs368811625
Type: single nucleotide variant
Location: chr2:43837873 (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 76: the abc transporter domain; a β-strand

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

Similar variants

ABCG5 p.Val76Leu Uncertain significance ★ ⚠ same residue
ABCG5 c.1325-1G>T 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
ABCG5 p.Arg243Ter Pathogenic ★★ same condition
ABCG5 p.Arg389His 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-val76met (accessed [today's date]).

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