ANKRD23

Chr 2

ankyrin repeat domain 23

Also known as: DARP, MARP3

NCBI Gene: 200539 ENSG00000163126 UniProt: Q86SG2 OMIM: 610736

The protein is a nuclear transcriptional regulator that may link myofibrillar stretch-induced signaling to muscle gene expression and energy metabolism. Mutations cause autosomal recessive dilated cardiomyopathy with left ventricular noncompaction. This gene is not highly constrained against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the muscle ankyrin repeat protein (MARP) family and encodes a protein with four tandem ankyrin-like repeats. The protein is localized to the nucleus, functioning as a transcriptional regulator. Expression of this protein is induced during recovery following starvation. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.88

Clinical Summary— ANKRD23

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

56 VUS of 68 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.88LOEUF

pLI 0.000

Z-score -1.62

OE 1.43 (1.03–1.88)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.58Z-score

OE missense 0.88 (0.77–1.00)

154 obs / 175.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.43 (1.03–1.88)

0≤0.351.4

Missense OE?0.88 (0.77–1.00)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 24 / 16.8Missense obs/exp: 154 / 175.6Syn Z: 0.51

This gene — mechanism propensity

0.6357th %ile

GOF

0.72top 25%

LOF

0.4134th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

68 submitted variants in ClinVar

ClinVar

Classification Summary

VUS56

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	56	56
Likely Benign	4	4
Benign	0	0
Total	60	60

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

31 pathogenic / likely-pathogenic (of 63) ClinVar copy-number / structural variants overlap ANKRD23 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →