Is ABCG2 p.Val445Leu (c.1333G>T) pathogenic?

ABCG2 p.Val445Leu (c.1333G>T) is classified Uncertain significance in ABCG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.4352); Very rare (popmax 0.0022%, nfe).

How common is ABCG2 p.Val445Leu (c.1333G>T) in the general population?

ABCG2 p.Val445Leu (c.1333G>T) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about ABCG2 p.Val445Leu (c.1333G>T)?

AlphaMissense predicts ambiguous (score 0.4352) — an in-silico prediction, not a clinical call.

ABCG2 p.Val445Leu

c.1333G>T · VCV4144806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4352	ambiguous
REVEL	0.06	moderately benign-leaning
SaProt	LLR -4.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP 1.1
Regional constraint	o/e 1.01	unconstrained · MANE · 48 kb · p 0.73 · regional, not allelic
Overall
CADD	18.32	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 0.0022% European (non-Finnish) · 26/1,180,016 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00167% 27/1,613,982 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0022%	45,385
African / African-American	0.00134%	74,898

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: ABCG2
Protein: p.Val445Leu
Coding: c.1333G>T
MANE Select: NM_004827
Type: single nucleotide variant
Location: chr4:88101264 (GRCh38)
Gene constraint: LOEUF 1.308 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.54 · 29 PDB
Residue 445: an α-helix; the abc transmembrane type-2 domain

Full ABCG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCG2 p.Tyr123= Benign ★★ same type
ABCG2 p.Ala505Gly Uncertain significance ★ ⚠ same type
ABCG2 p.Arg575Gln Uncertain significance ★ ⚠ same type
ABCG2 p.Asn289Lys Uncertain significance ★ ⚠ same type
ABCG2 p.Asp312Gly Uncertain significance ★ ⚠ same type
ABCG2 p.Asp419Tyr Uncertain significance ★ ⚠ same type
ABCG2 p.Gln324His Uncertain significance ★ ⚠ same type
ABCG2 p.Gln393Arg 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/abcg2-p-val445leu (accessed [today's date]).

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