Is ABCC9 p.Thr641Ala (c.1921A>G) pathogenic?

ABCC9 p.Thr641Ala (c.1921A>G) is classified Uncertain significance in ABCC9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0574); Very rare (popmax 0.0022%, sas); Associated with dilated cardiomyopathy 1O.

What condition is associated with ABCC9 p.Thr641Ala (c.1921A>G)?

ABCC9 p.Thr641Ala (c.1921A>G) is associated with dilated cardiomyopathy 1O (ClinVar).

How common is ABCC9 p.Thr641Ala (c.1921A>G) in the general population?

ABCC9 p.Thr641Ala (c.1921A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCC9 p.Thr641Ala (c.1921A>G)?

AlphaMissense predicts likely benign (score 0.0574) — an in-silico prediction, not a clinical call.

ABCC9 p.Thr641Ala

c.1921A>G · rs755145193 · VCV2887475

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1O

Computational evidence

Protein change
AlphaMissense	0.0574	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -6.71	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 2.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 45 kb · p 0.00018 · regional, not allelic
Overall
CADD	15.69	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 0.0022% South Asian · 2/91,068 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.00031% 5/1,612,896 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,534
African / African-American	0.00134%	74,892
European (non-Finnish)	0.00017%	589,532

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.Thr641Ala
Coding: c.1921A>G
MANE Select: NM_020297
dbSNP: rs755145193
Type: single nucleotide variant
Location: chr12:21882864 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.72

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

Disease context

dilated cardiomyopathy 1O — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ABCC9 p.Thr641Pro Uncertain significance ★ ⚠ same residue
ABCC9 p.Thr641= Likely benign ★ same residue
ABCC9 c.2506-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC9 p.Arg1116Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCC9 p.Arg1116His Pathogenic ★★ ⚠ same condition
ABCC9 p.Arg1154Gln Pathogenic ★★ ⚠ same condition
ABCC9 p.Arg1154Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCC9 p.Gln852Ter Pathogenic/Likely pathogenic ★★ 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-thr641ala (accessed [today's date]).

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