Is ABCG8 p.Pro74Ala (c.220C>G) pathogenic?

ABCG8 p.Pro74Ala (c.220C>G) is classified Uncertain significance in ABCG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-05). AlphaMissense: likely benign (0.1168); Ultra-rare (popmax 0.0373%, sas); Associated with sitosterolemia 1.

What condition is associated with ABCG8 p.Pro74Ala (c.220C>G)?

ABCG8 p.Pro74Ala (c.220C>G) is associated with sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Pro74Ala (c.220C>G) in the general population?

ABCG8 p.Pro74Ala (c.220C>G) is ultra-rare (popmax 0.0373%, sas) (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 ABCG8 p.Pro74Ala (c.220C>G)?

AlphaMissense predicts likely benign (score 0.1168) — an in-silico prediction, not a clinical call.

ABCG8 p.Pro74Ala

c.220C>G · rs373610655 · VCV336065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1168 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

sitosterolemia 1

Computational evidence

Protein change
AlphaMissense	0.1168	likely benign
REVEL	0.558	indeterminate
SaProt	LLR -8.03	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 2.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	23.2	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 0.0373% South Asian · 34/91,080 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.00948% 153/1,613,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.122%	822
South Asiangrpmax	0.0373%	2,679
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.00619%	16,165
Admixed American	0.00167%	59,996
African / African-American	0.00133%	74,912

Ashkenazi Jewish 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: ABCG8
Protein: p.Pro74Ala
Coding: c.220C>G
MANE Select: NM_022437
dbSNP: rs373610655
Type: single nucleotide variant
Location: chr2:43846209 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 8 PDB
Residue 74: the abc transporter domain

Full ABCG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

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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-pro74ala (accessed [today's date]).

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