Is ABCG1 p.Phe640Leu (c.1918T>C) pathogenic?

ABCG1 p.Phe640Leu (c.1918T>C) is classified Uncertain significance in ABCG1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-08). AlphaMissense: likely pathogenic (0.9072); Absent from gnomAD v4.1; Associated with ABCG1-related disorder.

What condition is associated with ABCG1 p.Phe640Leu (c.1918T>C)?

ABCG1 p.Phe640Leu (c.1918T>C) is associated with ABCG1-related disorder (ClinVar).

How common is ABCG1 p.Phe640Leu (c.1918T>C) in the general population?

ABCG1 p.Phe640Leu (c.1918T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCG1 p.Phe640Leu (c.1918T>C)?

AlphaMissense predicts likely pathogenic (score 0.9072) — an in-silico prediction, not a clinical call.

ABCG1 p.Phe640Leu

c.1918T>C · VCV3345639

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9072 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCG1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9072	likely pathogenic
REVEL	0.254	benign-leaning
SaProt	LLR -10.61	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 6,289 bp · p 2.8e-11 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F652L vs ClinVar F640L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCG1
Protein: p.Phe640Leu
Coding: c.1918T>C
MANE Select: NM_016818
Type: single nucleotide variant
Location: chr21:42296309 (GRCh38)
Gene constraint: LOEUF 0.573 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 81.34 · 5 PDB
Residue 640: the abc transmembrane type-2 domain; an α-helix

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

Disease context

ABCG1-related disorder

Similar variants

ABCG1 c.538-6C>T Benign same condition
ABCG1 p.Ala203= Likely benign same condition
ABCG1 p.Asp614= Likely benign same condition
ABCG1 p.Cys3= Benign same condition
ABCG1 p.Gly331= Benign same condition
ABCG1 p.Gly358Arg Benign same condition
ABCG1 p.Leu113= Benign same condition
ABCG1 p.Phe448= Likely benign 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/abcg1-p-phe640leu (accessed [today's date]).

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