Is ABCG5 p.Arg61Trp (c.181C>T) pathogenic?

ABCG5 p.Arg61Trp (c.181C>T) is classified Uncertain significance in ABCG5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-27). AlphaMissense: likely benign (0.074); Ultra-rare (popmax 0.0165%, mid); Associated with sitosterolemia.

What condition is associated with ABCG5 p.Arg61Trp (c.181C>T)?

ABCG5 p.Arg61Trp (c.181C>T) is associated with sitosterolemia (ClinVar).

How common is ABCG5 p.Arg61Trp (c.181C>T) in the general population?

ABCG5 p.Arg61Trp (c.181C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Sitosterolemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCG5 p.Arg61Trp (c.181C>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

ABCG5 p.Arg61Trp

c.181C>T · rs766545187 · VCV598505

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sitosterolemia

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.54 · evaluated, not missing
Constraint at this position
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	13.02	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00149% 24/1,613,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
African / African-American	0.00668%	14,976
East Asian	0.00223%	44,870
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.00127%	78,665
South Asian	0.0011%	91,068

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.Arg61Trp
Coding: c.181C>T
MANE Select: NM_022436
dbSNP: rs766545187
Type: single nucleotide variant
Location: chr2:43837918 (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 61: the abc transporter domain

Full ABCG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

ABCG5 p.Arg61Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCG5 p.Arg61= Likely benign ★ same residue
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-arg61trp (accessed [today's date]).

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