Is ABCG5 p.Arg157Cys (c.469C>T) pathogenic?

ABCG5 p.Arg157Cys (c.469C>T) is classified Uncertain significance in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely benign (0.1015); Very rare (popmax 0.000342%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ABCG5 p.Arg157Cys (c.469C>T)?

ABCG5 p.Arg157Cys (c.469C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCG5 p.Arg157Cys (c.469C>T) in the general population?

ABCG5 p.Arg157Cys (c.469C>T) is very rare (popmax 0.000342%, nfe) (gnomAD).

What do computational predictors say about ABCG5 p.Arg157Cys (c.469C>T)?

AlphaMissense predicts likely benign (score 0.1015) — an in-silico prediction, not a clinical call.

ABCG5 p.Arg157Cys

c.469C>T · rs2466090264 · VCV2625953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000342%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1015	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -7.10	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 1.3	GERP -3.5, phastCons 0.072
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	21.4	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 0.000342% European (non-Finnish) · 4/1,170,174 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000348% 5/1,437,206 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,650
European (non-Finnish)grpmax	0.000342%	292,543

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg157Cys
Coding: c.469C>T
MANE Select: NM_022436
dbSNP: rs2466090264
Type: single nucleotide variant
Location: chr2:43831801 (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 157: the abc transporter domain

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

Similar variants

ABCG5 p.Arg157His Uncertain significance ★ ⚠ same residue
ABCG5 c.1325-1G>T Likely pathogenic ★★ same condition
ABCG5 p.Gln251Ter Pathogenic ★★ same condition
ABCG5 p.Glu146Ter Pathogenic ★★ same condition
ABCG5 p.Ala170Asp Uncertain significance ★★ ⚠ same condition
ABCG5 p.Ala264Val Uncertain significance ★★ ⚠ same condition
ABCG5 p.Ala278Glu Uncertain significance ★★ ⚠ same condition
ABCG5 p.Ala333Ser 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/abcg5-p-arg157cys (accessed [today's date]).

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