Is COMT p.His62= (c.186C>T) pathogenic?

COMT p.His62= (c.186C>T) is classified Benign in COMT (ClinVar, Multiple submitters, 8 submitters; last evaluated 2021-05-04). Common (popmax 51.7%, nfe) — too common for a highly-penetrant pathogenic allele.

COMT p.His62=

Q: How common is COMT p.His62= (c.186C>T) in the general population?

COMT p.His62= (c.186C>T) is common (popmax 51.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.186C>T · rs4633 · VCV256785

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 51.7%, 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 -11	GERP -3.5
Overall
CADD	0.723	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 51.7% European (non-Finnish) · 609,772/1,179,774 alleles

Filtering AF 51.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 51.5%

Overall 49.2% 794,478/1,613,292 alleles · common exomes 726,681/1,461,162 · genomes 67,797/152,130 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	66.4%	2
Finnishnot grpmax-eligible	54.7%	2
European (non-Finnish)grpmax	51.7%	2
Middle Eastern	50.6%	2
Ashkenazi Jewishnot grpmax-eligible	46.9%	2
Remaining individualsnot grpmax-eligible	46.6%	2
South Asian	45.7%	2
Admixed American	40.8%	2
African / African-American	32.9%	3
East Asian	27.8%	4

Amish 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.His62=
Coding: c.186C>T
MANE Select: NM_000754
dbSNP: rs4633
Type: single nucleotide variant
Location: chr22:19962712 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.07 · 12 PDB
Residue 62: an α-helix

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-his62 (accessed [today's date]).

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