AMDHD2

Chr 16

amidohydrolase domain containing 2

Also known as: CGI-14

NCBI Gene: 51005 ENSG00000162066 UniProt: Q9Y303

The protein hydrolyzes N-glycolyl groups from N-glycolylglucosamine 6-phosphate in the N-glycolylneuraminic acid degradation pathway, processing dietary N-glycolylneuraminic acid that humans cannot synthesize but must degrade. Mutations cause autosomal recessive developmental and epileptic encephalopathy with brain atrophy and abnormal neuronal migration. The gene shows low constraint to loss-of-function variants.

ResearchSummary from RefSeq, UniProt

Enables N-acetylglucosamine-6-phosphate deacetylase activity. Involved in negative regulation of UDP-N-acetylglucosamine biosynthetic process. Located in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.81

Clinical Summary— AMDHD2

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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

1 unique Pathogenic / Likely Pathogenic· 99 VUS of 112 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.002

Z-score 2.12

OE 0.43 (0.24–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.52Z-score

OE missense 0.92 (0.84–1.01)

341 obs / 369.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.24–0.81)

0≤0.351.4

Missense OE?0.92 (0.84–1.01)

0≤0.61.4

Synonymous OE?1.37

0≤1.21.6

LoF obs/exp: 7 / 16.2Missense obs/exp: 341 / 369.1Syn Z: -3.74

This gene — mechanism propensity

0.7227th %ile

GOF

0.6542th %ile

LOF

0.2873th %ile

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

DNprediction above median

GOFprediction 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

112 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS99

Likely Benign6

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	1	0	1
VUS	1	98	0	99
Likely Benign	0	5	1	6
Benign	0	0	0	0
Total	1	104	1	106

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap AMDHD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →