# NM_020297.4(ABCC9):c.201G>A (p.Pro67=)

https://sugi.bio/variant/abcc9-p-pro67

## Summary

**ABCC9 p.Pro67= (c.201G>A)** is classified **Likely benign** in ABCC9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-16). Very rare (popmax 0.00195%, nfe); Associated with dilated cardiomyopathy 1O.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs769322587 · 2 submitters · 1 linked condition · very rare (popmax 0.00195%, nfe)

## For patients & families {#patients}

This is a change in the ABCC9 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to dilated cardiomyopathy 1O.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | ABCC9 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Familial isolated dilated cardiomyopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dilated cardiomyopathy — Very frequent (99-80%)
- Left ventricular systolic dysfunction — Very frequent (99-80%)
- Edema — Frequent (79-30%)
- Congestive heart failure — Frequent (79-30%)
- Exertional dyspnea — Frequent (79-30%)
- Arrhythmia — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Orthopnea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015434/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCC9](https://sugi.bio/atlas/gene/ABCC9/) |
| Protein change (HGVS p.) | p.Pro67= |
| Coding change (HGVS c.) | c.201G>A |
| MANE Select transcript | [NM_020297](https://www.ncbi.nlm.nih.gov/nuccore/NM_020297) |
| dbSNP | [rs769322587](https://www.ncbi.nlm.nih.gov/snp/rs769322587/) |
| Variant type | single nucleotide variant |
| Location | chr12:21933865-21933865 (GRCh38) |
| ClinVar | [VCV1010707](https://www.ncbi.nlm.nih.gov/clinvar/variation/1010707/) |

**All HGVS expressions:** `LRG_377:g.7830G>A`, `LRG_377t2:c.201G>A`, `NC_000012.11:g.22086799C>T`, `NC_000012.12:g.21933865C>T`, `NG_012819.1:g.7830G>A`, `NM_001377273.1:c.201G>A`, `NM_001377274.1:c.-254G>A`, `NM_005691.4:c.201G>A`, `NM_020297.4:c.201G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.113, GERP -3.71, phastCons 0.006 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 14.95**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00195%** (nfe) · FAF95 0.0013% · FAF99 0.00108% · 23/1,179,682 in the highest group · 24/1,613,466 alleles overall — very rare (popmax 0.00195%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00195% | 51,290 |
| South Asian | 0.0011% | 91,066 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ABCC9** population constraint: LOEUF 0.557, pLI 7.2745e-06, missense-Z 7.0369. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Brugada syndrome** — Disputed (AD)
- **hypertrichotic osteochondrodysplasia Cantu type** — Definitive (AD)
- **dilated cardiomyopathy 1O** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.72, 35% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ABCC9 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ABCC9's established molecular role includes ATPase-coupled transmembrane transporter activity. In Reactome, ABCC9 is annotated in disease pathway(s) including **Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome**.

**Disease mechanism (Reactome):** ABCC9 loss or alteration is curated in [Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome](https://reactome.org/content/detail/R-HSA-5678420).

### Pathways affected {#pathways}

ABCC9 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome](https://reactome.org/content/detail/R-HSA-5678420) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [ATP sensitive Potassium channels](https://reactome.org/content/detail/R-HSA-1296025) | curated |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ATPase-coupled transmembrane transporter activity, transmembrane transporter binding.

**Biological process:** response to ATP, defense response to virus, cardiac conduction, potassium ion transmembrane transport.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-16.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-16 |

## Associated conditions {#conditions}

[dilated cardiomyopathy 1O](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1o/).

**Reported phenotype names (ClinVar):** Dilated cardiomyopathy 1O, Cardiovascular phenotype, CARDIOMYOPATHY, DILATED, WITH VENTRICULAR TACHYCARDIA.

## Similar variants {#similar}

Related ABCC9 variant pages (same residue, condition, or type): [ABCC9 p.Pro67Leu](/variant/abcc9-p-pro67leu), [ABCC9 c.2506-1G>A](/variant/abcc9-c-2506-minus-1g-a), [ABCC9 p.Arg1116Cys](/variant/abcc9-p-arg1116cys), [ABCC9 p.Arg1116His](/variant/abcc9-p-arg1116his), [ABCC9 p.Arg1154Gln](/variant/abcc9-p-arg1154gln), [ABCC9 p.Arg1154Trp](/variant/abcc9-p-arg1154trp), [ABCC9 p.Gln852Ter](/variant/abcc9-p-gln852ter), [ABCC9 p.Thr1202Met](/variant/abcc9-p-thr1202met).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1010707). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*