ALG14

Chr 1AR

ALG14 UDP-N-acetylglucosaminyltransferase subunit

Also known as: CMS15, IDDEBF, MEPCA

NCBI Gene: 199857 ENSG00000172339 UniProt: Q96F25 OMIM: 612866

The protein forms a subunit of UDP-GlcNAc transferase with ALG13, catalyzing the first two committed steps in endoplasmic reticulum N-linked glycosylation. Autosomal recessive mutations cause congenital myasthenic syndrome without tubular aggregates, intellectual developmental disorder with epilepsy and behavioral abnormalities, or myopathy with epilepsy and progressive cerebral atrophy. The pathogenic mechanism appears to involve dominant-negative effects disrupting the glycosylation pathway.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the glycosyltransferase 1 family. The encoded protein and ALG13 are thought to be subunits of UDP-GlcNAc transferase, which catalyzes the first two committed steps in endoplasmic reticulum N-linked glycosylation. Mutations in this gene have been linked to congenital myasthenic syndrome (CMSWTA). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.203 OMIM phenotypes

Clinical Summary— ALG14

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Gene-Disease Validity (ClinGen)

congenital disorder of glycosylation · ARLimited

Limited evidence — not for standalone diagnostic reporting

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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· 92 VUS of 171 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ALG14

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.20LOEUF

pLI 0.001

Z-score 1.15

OE 0.61 (0.33–1.20)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.27Z-score

OE missense 0.93 (0.80–1.09)

118 obs / 126.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.33–1.20)

0≤0.351.4

Missense OE?0.93 (0.80–1.09)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 6 / 9.9Missense obs/exp: 118 / 126.4Syn Z: 0.55

This gene — mechanism propensity

0.7035th %ile

GOF

0.6345th %ile

LOF

0.2970th %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

171 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS92

Likely Benign64

Benign7

Conflicting7

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	6	82	4	0	92
Likely Benign	0	8	25	31	64
Benign	0	1	5	1	7
Conflicting	—				7
Total	6	92	34	32	171

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap ALG14 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →