Is ABCC9 p.Phe42Cys (c.125T>G) pathogenic?

ABCC9 p.Phe42Cys (c.125T>G) is classified Uncertain significance in ABCC9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-24). AlphaMissense: likely pathogenic (0.8256); Very rare (popmax 0.0011%, sas); Associated with dilated cardiomyopathy 1O.

What condition is associated with ABCC9 p.Phe42Cys (c.125T>G)?

ABCC9 p.Phe42Cys (c.125T>G) is associated with dilated cardiomyopathy 1O (ClinVar).

How common is ABCC9 p.Phe42Cys (c.125T>G) in the general population?

ABCC9 p.Phe42Cys (c.125T>G) is very rare (popmax 0.0011%, 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.Phe42Cys (c.125T>G)?

AlphaMissense predicts likely pathogenic (score 0.8256) — an in-silico prediction, not a clinical call.

ABCC9 p.Phe42Cys

c.125T>G · VCV4077775

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8256 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1O

Computational evidence

Protein change
AlphaMissense	0.8256	likely pathogenic
REVEL	0.772	pathogenic-leaning
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 29 kb · p 4.3e-29 · regional, not allelic
Overall
CADD	27.0	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 0.0011% South Asian · 1/91,012 alleles

Overall 6.85e-05% 1/1,460,676 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.Phe42Cys
Coding: c.125T>G
MANE Select: NM_020297
Type: single nucleotide variant
Location: chr12:21936550 (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 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
ABCC9 p.Thr1202Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCC9 p.Val1266Met 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-phe42cys (accessed [today's date]).

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