ANKRD37

Chr 4

ankyrin repeat domain 37

Also known as: Lrp2bp

NCBI Gene: 353322 ENSG00000186352 UniProt: Q7Z713 OMIM: 619021

The ANKRD37 protein localizes to the cytosol, mitochondria, and nucleus, though its specific molecular function remains unclear. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, typically presenting in infancy with seizures and severe developmental delays. The gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq

Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.34

Clinical Summary— ANKRD37

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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

2 unique Pathogenic / Likely Pathogenic· 25 VUS of 33 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?

1.34LOEUF

pLI 0.001

Z-score 0.87

OE 0.68 (0.37–1.34)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.24Z-score

OE missense 1.07 (0.91–1.27)

94 obs / 87.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.68 (0.37–1.34)

0≤0.351.4

Missense OE?1.07 (0.91–1.27)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 6 / 8.8Missense obs/exp: 94 / 87.7Syn Z: 0.03

This gene — mechanism propensity

0.6550th %ile

GOF

0.73top 25%

LOF

0.3261th %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

33 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS25

Likely Benign1

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	2	2
VUS	25	25
Likely Benign	1	1
Benign	0	0
Total	28	28

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

View in ClinVar →

116 pathogenic / likely-pathogenic (of 142) ClinVar copy-number / structural variants overlap ANKRD37 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →