PCMTD2

Chr 20

protein-L-isoaspartate (D-aspartate) O-methyltransferase domain containing 2

Also known as: C20orf36

NCBI Gene: 55251 ENSG00000203880 UniProt: Q9NV79 OMIM: 620077

The protein is predicted to function as a protein-L-isoaspartate O-methyltransferase involved in protein modification and may also act as a substrate recognition component of an E3 ubiquitin ligase complex that targets proteins for degradation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, seizures, and progressive neurodegeneration. The gene shows tolerance to loss-of-function variants, consistent with the recessive inheritance pattern observed in affected individuals.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable protein-L-isoaspartate (D-aspartate) O-methyltransferase activity. Predicted to be involved in protein modification process. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.78

Clinical Summary— PCMTD2

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.008

Z-score 2.18

OE 0.40 (0.22–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.52Z-score

OE missense 0.71 (0.62–0.81)

151 obs / 213.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.22–0.78)

0≤0.351.4

Missense OE?0.71 (0.62–0.81)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 6 / 15.2Missense obs/exp: 151 / 213.5Syn Z: 0.68

This gene — mechanism propensity

0.6358th %ile

GOF

0.6344th %ile

LOF

0.3067th %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.