Is COMT p.Pro69= (c.207C>T) pathogenic?

COMT p.Pro69= (c.207C>T) is classified Likely benign in COMT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-19). Very rare (popmax 0.00669%, eas); Associated with COMT-related disorder.

What condition is associated with COMT p.Pro69= (c.207C>T)?

COMT p.Pro69= (c.207C>T) is associated with COMT-related disorder (ClinVar).

How common is COMT p.Pro69= (c.207C>T) in the general population?

COMT p.Pro69= (c.207C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

COMT p.Pro69=

c.207C>T · rs745542046 · VCV3046309

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Conditions

COMT-related disorder

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 -6.3	GERP -3.5
Overall
CADD	4.085	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,872 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000682% 11/1,613,698 alleles · very rare exomes 11/1,461,406 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
Admixed American	0.00333%	30,006
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	0.000339%	294,993

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.Pro69=
Coding: c.207C>T
MANE Select: NM_000754
dbSNP: rs745542046
Type: single nucleotide variant
Location: chr22:19962733 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.07 · 12 PDB

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

Disease context

COMT-related disorder

Similar variants

COMT c.1-5T>C Likely benign same condition
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

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-pro69 (accessed [today's date]).

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