Is COMT p.Ala72Ser (c.214G>T) pathogenic?

COMT p.Ala72Ser (c.214G>T) is classified Uncertain significance in COMT (ClinVar, Single submitter, 3 submitters; last evaluated 2022-10-10). AlphaMissense: likely benign (0.119); Common (popmax 6.81%, eas) — too common for a highly-penetrant pathogenic allele; Associated with 22q11.2 deletion syndrome.

What condition is associated with COMT p.Ala72Ser (c.214G>T)?

COMT p.Ala72Ser (c.214G>T) is associated with 22q11.2 deletion syndrome, schizophrenia, susceptibility to (ClinVar).

What do computational predictors say about COMT p.Ala72Ser (c.214G>T)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

COMT p.Ala72Ser

Q: How common is COMT p.Ala72Ser (c.214G>T) in the general population?

COMT p.Ala72Ser (c.214G>T) is common (popmax 6.81%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.214G>T · rs6267 · VCV17592

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.81%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

22q11.2 deletion syndrome

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 6,206 bp · p 0.085 · regional, not allelic
Overall
CADD	19.31	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.81% East Asian · 3,058/44,872 alleles

Filtering AF 6.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.53%

Overall 0.562% 9,067/1,613,680 alleles · common exomes 7,753/1,461,360 · genomes 1,314/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	6.81%	15
Finnishnot grpmax-eligible	4.53%	22
Admixed American	3.36%	30
Remaining individualsnot grpmax-eligible	0.47%	213
South Asian	0.171%	584
Amishnot grpmax-eligible	0.11%	912
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
European (non-Finnish)	0.051%	1,960
Middle Eastern	0.0495%	2,021
African / African-American	0.0426%	2,345

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.Ala72Ser
Coding: c.214G>T
MANE Select: NM_000754
dbSNP: rs6267
Type: single nucleotide variant
Location: chr22:19962740 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.07 · 12 PDB
Residue 72: a UniProt-annotated variant site (correlated with reduced enzyme activity; associated with increased risk for schizophrenia); an α-helix

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

Disease context

22q11.2 deletion syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: schizophrenia, susceptibility to

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-ala72ser (accessed [today's date]).

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