# NM_000754.4(COMT):c.408C>G (p.Leu136=)

https://sugi.bio/variant/comt-p-leu136

## Summary

**COMT p.Leu136= (c.408C>G)** is classified **Benign** in COMT (ClinVar, Multiple submitters, 9 submitters; last evaluated 2021-05-04). Common (popmax 40.1%, nfe) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs4818 · 9 submitters · common (popmax 40.1%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the COMT gene that is classified as benign — not considered disease-causing, submitted by 9 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COMT](https://sugi.bio/atlas/gene/COMT/) |
| Protein change (HGVS p.) | p.Leu136= |
| Coding change (HGVS c.) | c.408C>G |
| MANE Select transcript | [NM_000754](https://www.ncbi.nlm.nih.gov/nuccore/NM_000754) |
| dbSNP | [rs4818](https://www.ncbi.nlm.nih.gov/snp/rs4818/) |
| Variant type | single nucleotide variant |
| Location | chr22:19963684-19963684 (GRCh38) |
| ClinVar | [VCV256786](https://www.ncbi.nlm.nih.gov/clinvar/variation/256786/) |

**All HGVS expressions:** `LRG_1010:g.26945C>G`, `LRG_1010t1:c.408C>G`, `NC_000022.10:g.19951207C>G`, `NC_000022.11:g.19963684C>G`, `NG_011526.1:g.26945C>G`, `NM_000754.4:c.408C>G`, `NM_001135161.2:c.408C>G`, `NM_001135162.2:c.408C>G`, `NM_001362828.2:c.408C>G`, `NM_007310.3:c.258C>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 40.1%, nfe) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.378, GERP -2.11, phastCons 0.127 — weakly conserved position
- CADD: **PHRED 3.026**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **40.1%** (nfe) · FAF95 40% · FAF99 39.9% · 472,616/1,179,844 in the highest group · 604,581/1,612,472 alleles overall — common (popmax 40.1%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 46.1% | 2 |
| European (non-Finnish) (grpmax) | 40.1% | 2 |
| Middle Eastern | 37.8% | 3 |
| Remaining individuals (not grpmax-eligible) | 37.7% | 3 |
| South Asian | 31.9% | 3 |
| Finnish (not grpmax-eligible) | 31.2% | 3 |
| East Asian | 31% | 3 |
| Amish (not grpmax-eligible) | 30.6% | 3 |
| Admixed American | 24.2% | 4 |
| African / African-American | 20.2% | 5 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**COMT** population constraint: LOEUF 1.128, pLI 0.00049821, missense-Z 0.73971. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **136** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.07, 81% of residues very-high.

**12 experimental structure(s)** (PDB): [3A7E](https://www.rcsb.org/structure/3A7E), [3BWM](https://www.rcsb.org/structure/3BWM), [3BWY](https://www.rcsb.org/structure/3BWY), [4PYI](https://www.rcsb.org/structure/4PYI), [4PYJ](https://www.rcsb.org/structure/4PYJ), [4PYK](https://www.rcsb.org/structure/4PYK).

## What this gene does {#gene-function}

*Describes the biological roles of COMT (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** COMT's established molecular role includes catechol O-methyltransferase activity. In Reactome, COMT is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** COMT loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

COMT participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [Enzymatic degradation of Dopamine by monoamine oxidase](https://reactome.org/content/detail/R-HSA-379398) | curated |
| [Enzymatic degradation of dopamine by COMT](https://reactome.org/content/detail/R-HSA-379397) | curated |
| [Methylation](https://reactome.org/content/detail/R-HSA-156581) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** catechol O-methyltransferase activity.

**Biological process:** methylation, catecholamine catabolic process.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-05-04.

**Submitter consensus:** conflicting (7 Benign, 1 drug response, 1 Uncertain risk allele).

**Submission history:** 9 submissions (2018–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Bruce Budowle Laboratory, University of North Texas Health Science Center | drug response | no assertion criteria provided | research | 2018-04-28 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-05-04 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology | Uncertain risk allele | no assertion criteria provided | case-control | 2023-01-16 |

**Reported phenotype names (ClinVar):** not specified, Tramadol response, methamphetamine use disorder, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided, Ultram response, AllHighlyPenetrant.

## Pharmacogenomics (PharmGKB) {#pgx}

Clinical drug-response annotations:

| Drug(s) | Evidence level | Category | Phenotype |
| --- | --- | --- | --- |
| opioids | 3 | Other | Pain |
| quetiapine | 3 | Efficacy | Schizophrenia |
| risperidone | 3 | Efficacy | Schizophrenia |
*PharmGKB levels 1A/1B (highest) → 4. Discuss any medication decision with your prescriber — reference information, not advice.*

## Similar variants {#similar}

Related COMT variant pages (same residue, condition, or type): [TXNRD2 p.Ala5Val](/variant/txnrd2-p-ala5val), [TXNRD2 p.Ala7Gly](/variant/txnrd2-p-ala7gly), [TXNRD2 p.Ala7Val](/variant/txnrd2-p-ala7val), [TXNRD2 p.Arg9Pro](/variant/txnrd2-p-arg9pro), [TXNRD2 p.Gly10Ala](/variant/txnrd2-p-gly10ala), [TXNRD2 p.Gly10Val](/variant/txnrd2-p-gly10val), [TXNRD2 p.Leu8Val](/variant/txnrd2-p-leu8val), [TXNRD2 p.Met1Thr](/variant/txnrd2-p-met1thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 256786). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*