Is ABCC9 p.Ala559Thr (c.1675G>A) pathogenic?

ABCC9 p.Ala559Thr (c.1675G>A) is classified Uncertain significance in ABCC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-17). AlphaMissense: likely benign (0.1282); Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ABCC9 p.Ala559Thr (c.1675G>A)?

ABCC9 p.Ala559Thr (c.1675G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCC9 p.Ala559Thr (c.1675G>A) in the general population?

ABCC9 p.Ala559Thr (c.1675G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ABCC9 p.Ala559Thr (c.1675G>A)?

AlphaMissense predicts likely benign (score 0.1282) — an in-silico prediction, not a clinical call.

ABCC9 p.Ala559Thr

c.1675G>A · VCV4840036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1282 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1282	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -4.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 45 kb · p 0.00018 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,968 alleles

Overall 6.84e-05% 1/1,461,754 alleles · very rare

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: ABCC9
Protein: p.Ala559Thr
Coding: c.1675G>A
MANE Select: NM_020297
Type: single nucleotide variant
Location: chr12:21894159 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.72
Residue 559: the abc transmembrane type-1 1 domain

Full ABCC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCC9 p.Ala559= Benign/Likely benign ★★ same residue
ABCC9 p.Ala559Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC9 c.2092+5G>T Uncertain significance ★★ same condition
ABCC9 c.3893-3C>T Uncertain significance ★★ same condition
ABCC9 c.4512+693G>A Uncertain significance ★★ ⚠ same condition
ABCC9 c.4512+733C>A Uncertain significance ★★ ⚠ same condition
ABCC9 p.Ala136Ser Uncertain significance ★★ same condition
ABCC9 p.Ala276Thr Uncertain significance ★★ ⚠ 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/abcc9-p-ala559thr (accessed [today's date]).

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