Is ABCG5 p.Leu637Pro (c.1910T>C) pathogenic?

ABCG5 p.Leu637Pro (c.1910T>C) is classified Uncertain significance in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-18). AlphaMissense: ambiguous (0.4467); Ultra-rare (popmax 0.0215%, sas).

How common is ABCG5 p.Leu637Pro (c.1910T>C) in the general population?

ABCG5 p.Leu637Pro (c.1910T>C) is ultra-rare (popmax 0.0215%, sas) (gnomAD).

What do computational predictors say about ABCG5 p.Leu637Pro (c.1910T>C)?

AlphaMissense predicts ambiguous (score 0.4467) — an in-silico prediction, not a clinical call.

ABCG5 p.Leu637Pro

c.1910T>C · rs745775861 · VCV2577149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4467 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0215%, sas)

Computational evidence

Protein change
AlphaMissense	0.4467	ambiguous
REVEL	0.483	indeterminate
SaProt	LLR -12.39	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0215% South Asian · 19/88,182 alleles

Filtering AF 0.014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0117%

Overall 0.00136% 20/1,474,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0215%	4,641
European (non-Finnish)	9.49e-05%	1,053,668

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.Leu637Pro
Coding: c.1910T>C
MANE Select: NM_022436
dbSNP: rs745775861
Type: single nucleotide variant
Location: chr2:43813162 (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 637: the abc transmembrane type-2 domain; an α-helix

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

Similar variants

ABCG5 c.1325-1G>T Likely pathogenic ★★ same type
ABCG5 c.1464-1G>C Pathogenic/Likely pathogenic ★★ same type
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCG5 c.634+1G>C Likely pathogenic ★★ same type
ABCG5 c.904+1G>A Pathogenic ★★ same type
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same type
ABCG5 p.Arg243Ter Pathogenic ★★ same type
ABCG5 p.Arg389His 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/abcg5-p-leu637pro (accessed [today's date]).

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