Is COMT p.Leu136= (c.408C>G) pathogenic?

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.

COMT p.Leu136=

Q: How common is COMT p.Leu136= (c.408C>G) in the general population?

COMT p.Leu136= (c.408C>G) is common (popmax 40.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.408C>G · rs4818 · VCV256786

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 40.1%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -2.1, phastCons 0.13
Overall
CADD	3.026	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 40.1% European (non-Finnish) · 472,616/1,179,844 alleles

Filtering AF 40% ClinGen BA1/BS1 input FAF95, joint · FAF99 39.9%

Overall 37.5% 604,581/1,612,472 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	46.1%	2
European (non-Finnish)grpmax	40.1%	2
Middle Eastern	37.8%	3
Remaining individualsnot grpmax-eligible	37.7%	3
South Asian	31.9%	3
Finnishnot grpmax-eligible	31.2%	3
East Asian	31%	3
Amishnot 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 above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COMT
Protein: p.Leu136=
Coding: c.408C>G
MANE Select: NM_000754
dbSNP: rs4818
Type: single nucleotide variant
Location: chr22:19963684 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.07 · 12 PDB
Residue 136: a β-strand

Full COMT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TXNRD2 p.Ala5Val Uncertain significance ★★ same type
TXNRD2 p.Ala7Gly Uncertain significance ★★ same type
TXNRD2 p.Ala7Val Uncertain significance ★★ same type
TXNRD2 p.Arg9Pro Uncertain significance ★★ same type
TXNRD2 p.Gly10Ala Uncertain significance ★★ same type
TXNRD2 p.Gly10Val Uncertain significance ★★ same type
TXNRD2 p.Leu8Val Uncertain significance ★★ same type
TXNRD2 p.Met1Thr Uncertain significance ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/comt-p-leu136 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown