Is ABCC9 p.Arg189Gln (c.566G>A) pathogenic?

ABCC9 p.Arg189Gln (c.566G>A) is classified Uncertain significance in ABCC9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-19). AlphaMissense: likely benign (0.1387); Very rare (popmax 0.00017%, nfe); Associated with hypertrichotic osteochondrodysplasia Cantu type.

What condition is associated with ABCC9 p.Arg189Gln (c.566G>A)?

ABCC9 p.Arg189Gln (c.566G>A) is associated with hypertrichotic osteochondrodysplasia Cantu type, dilated cardiomyopathy 1O (ClinVar).

How common is ABCC9 p.Arg189Gln (c.566G>A) in the general population?

ABCC9 p.Arg189Gln (c.566G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ABCC9 p.Arg189Gln (c.566G>A)?

AlphaMissense predicts likely benign (score 0.1387) — an in-silico prediction, not a clinical call.

ABCC9 p.Arg189Gln

c.566G>A · rs945226728 · VCV2726395

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrichotic osteochondrodysplasia Cantu type

Computational evidence

Protein change
AlphaMissense	0.1387	likely benign
REVEL	0.68	pathogenic-leaning
SaProt	LLR -7.89	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 29 kb · p 4.3e-29 · regional, not allelic
Overall
CADD	25.8	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 0.00017% European (non-Finnish) · 2/1,178,318 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,458,710 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.Arg189Gln
Coding: c.566G>A
MANE Select: NM_020297
dbSNP: rs945226728
Type: single nucleotide variant
Location: chr12:21916944 (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

hypertrichotic osteochondrodysplasia Cantu type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1O

Similar variants

ABCC9 p.Arg189Ter Conflicting classifications of pathogenicity ★ 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
ABCC9 p.Gly989Glu 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-arg189gln (accessed [today's date]).

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