ANKRD54

Chr 22

ankyrin repeat domain 54

Also known as: LIAR

NCBI Gene: 129138 ENSG00000100124 UniProt: Q6NXT1 OMIM: 613383

The ANKRD54 protein regulates intracellular signaling events during erythroid terminal differentiation and is predicted to have protein kinase regulator activity. Mutations cause autosomal recessive intellectual disability with seizures and growth retardation, typically presenting in early childhood. The gene shows low constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected individuals.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable protein kinase regulator activity. Predicted to be involved in positive regulation of erythrocyte differentiation and regulation of intracellular signal transduction. Predicted to act upstream of or within nucleocytoplasmic transport and regulation of protein kinase activity. Predicted to be located in midbody. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.83

Clinical Summary— ANKRD54

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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

39 VUS of 56 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.002

Z-score 2.06

OE 0.44 (0.25–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.93Z-score

OE missense 0.78 (0.67–0.92)

117 obs / 149.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.25–0.83)

0≤0.351.4

Missense OE?0.78 (0.67–0.92)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 7 / 15.9Missense obs/exp: 117 / 149.1Syn Z: -0.86

This gene — mechanism propensity

0.6743th %ile

GOF

0.6931th %ile

LOF

0.3453th %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

56 submitted variants in ClinVar

ClinVar

Classification Summary

VUS39

Likely Benign2

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	39	0	39
Likely Benign	2	0	2
Benign	0	1	1
Total	41	1	42

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap ANKRD54 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →