PCMTD2

Chr 20

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

Also known as: C20orf36

NCBI Gene: 55251ENSG00000203880UniProt: Q9NV79

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.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
2
Pubs (1 yr)
35
P/LP submissions
0%
P/LP missense
0.78
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— PCMTD2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
35 unique Pathogenic / Likely Pathogenic· 47 VUS of 91 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
0.78LOEUF
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 OE0.40 (0.22–0.78)
0≤0.351.4
Missense OE0.71 (0.62–0.81)
0≤0.61.4
Synonymous OE0.90
0≤1.21.6
LoF obs/exp: 6 / 15.2Missense obs/exp: 151 / 213.5Syn Z: 0.68
DN
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.

ClinVar Variant Classifications

91 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic6
VUS47
Likely Benign2
Benign2
29
Pathogenic
6
Likely Pathogenic
47
VUS
2
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
29
0
29
Likely Pathogenic
0
0
6
0
6
VUS
0
35
12
0
47
Likely Benign
0
1
1
0
2
Benign
0
0
2
0
2
Total03650086

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

View in ClinVar →

Protein Context — Lollipop Plot

PCMTD2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients