Is ABCG8 p.Pro44Thr (c.130C>A) pathogenic?

ABCG8 p.Pro44Thr (c.130C>A) is classified Uncertain significance in ABCG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.0164%, mid).

How common is ABCG8 p.Pro44Thr (c.130C>A) in the general population?

ABCG8 p.Pro44Thr (c.130C>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ABCG8 p.Pro44Thr (c.130C>A)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

ABCG8 p.Pro44Thr

c.130C>A · rs770421664 · VCV596053

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -7.81	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 2.2	GERP 0.41, phastCons 0.99
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	12.22	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00229% 37/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)	0.00195%	51,305

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.Pro44Thr
Coding: c.130C>A
MANE Select: NM_022437
dbSNP: rs770421664
Type: single nucleotide variant
Location: chr2:43844573 (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 44: an α-helix

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

Similar variants

ABCG8 c.64-2A>G Pathogenic ★★ same type
ABCG8 c.964+1G>T Likely pathogenic ★★ same type
ABCG8 c.965-1G>C Pathogenic ★★ same type
ABCG8 p.Arg121Ter Pathogenic ★★ same type
ABCG8 p.Arg164Ter Pathogenic ★★ same type
ABCG8 p.Arg405Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
ABCG8 p.Arg412Ter Pathogenic/Likely pathogenic ★★ same type
ABCG8 p.Gln271Ter Pathogenic/Likely pathogenic ★★ same type

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-pro44thr (accessed [today's date]).

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