Is ABCG2 p.Val449Ala (c.1346T>C) pathogenic?

ABCG2 p.Val449Ala (c.1346T>C) is classified Uncertain significance in ABCG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: ambiguous (0.3992); Very rare (popmax 0.00834%, amr).

How common is ABCG2 p.Val449Ala (c.1346T>C) in the general population?

ABCG2 p.Val449Ala (c.1346T>C) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about ABCG2 p.Val449Ala (c.1346T>C)?

AlphaMissense predicts ambiguous (score 0.3992) — an in-silico prediction, not a clinical call.

ABCG2 p.Val449Ala

c.1346T>C · VCV3308591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Computational evidence

Protein change
AlphaMissense	0.3992	ambiguous
REVEL	0.329	indeterminate
SaProt	LLR -7.40	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 2, phastCons 0.69
Regional constraint	o/e 1.01	unconstrained · MANE · 48 kb · p 0.73 · regional, not allelic
Overall
CADD	23.6	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 0.00834% Admixed American · 5/59,988 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000743% 12/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,998
Remaining individualsnot grpmax-eligible	0.008%	12,497
African / African-American	0.00133%	74,910
South Asian	0.0011%	91,084

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.Val449Ala
Coding: c.1346T>C
MANE Select: NM_004827
Type: single nucleotide variant
Location: chr4:88101251 (GRCh38)
Gene constraint: LOEUF 1.308 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.54 · 29 PDB
Residue 449: 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-val449ala (accessed [today's date]).

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