Is ABCG1 p.Pro563Leu (c.1688C>T) pathogenic?

ABCG1 p.Pro563Leu (c.1688C>T) is classified Uncertain significance in ABCG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely pathogenic (0.9821); Very rare (popmax 0.004%, afr).

How common is ABCG1 p.Pro563Leu (c.1688C>T) in the general population?

ABCG1 p.Pro563Leu (c.1688C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about ABCG1 p.Pro563Leu (c.1688C>T)?

AlphaMissense predicts likely pathogenic (score 0.9821) — an in-silico prediction, not a clinical call.

ABCG1 p.Pro563Leu

c.1688C>T · VCV3412366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9821	likely pathogenic
REVEL	0.736	pathogenic-leaning
SaProt	LLR -15.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 6,289 bp · p 2.8e-11 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P575L vs ClinVar P563L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,936 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00211% 34/1,614,100 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,979
European (non-Finnish)	0.00246%	40,691
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: ABCG1
Protein: p.Pro563Leu
Coding: c.1688C>T
MANE Select: NM_016818
Type: single nucleotide variant
Location: chr21:42294576 (GRCh38)
Gene constraint: LOEUF 0.573 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 81.34 · 5 PDB
Residue 563: the abc transmembrane type-2 domain; an α-helix

Full ABCG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCG1 p.Ala456= Benign ★★ same type
ABCG1 p.Leu643= Likely benign ★★ same type
ABCG1 p.Pro149= Benign ★★ same type
ABCG1 p.Ser547= Benign ★★ same type
ABCG1 c.1122+21A>C Uncertain significance ★ ⚠ same type
ABCG1 c.1122+24G>C Uncertain significance ★ ⚠ same type
ABCG1 c.1122+2T>C Uncertain significance ★ ⚠ same type
ABCG1 p.Ala546Thr Uncertain significance ★ ⚠ 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/abcg1-p-pro563leu (accessed [today's date]).

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