Is AOC2 p.Thr486Met (c.1457C>T) pathogenic?

AOC2 p.Thr486Met (c.1457C>T) is classified Uncertain significance in AOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: ambiguous (0.3664); Very rare (popmax 0.00336%, amr).

How common is AOC2 p.Thr486Met (c.1457C>T) in the general population?

AOC2 p.Thr486Met (c.1457C>T) is very rare (popmax 0.00336%, amr) (gnomAD).

What do computational predictors say about AOC2 p.Thr486Met (c.1457C>T)?

AlphaMissense predicts ambiguous (score 0.3664) — an in-silico prediction, not a clinical call.

AOC2 p.Thr486Met

c.1457C>T · rs140222638 · VCV3127363

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

Computational evidence

Protein change
AlphaMissense	0.3664	ambiguous
REVEL	0.622	indeterminate
SaProt	LLR -12.32	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.054, phastCons 0.98
Regional constraint	o/e 1.05	unconstrained · MANE · 5,718 bp · p 0.1 · regional, not allelic
Overall
CADD	24.2	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 0.00336% Admixed American · 2/59,530 alleles

Filtering AF 0.00233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00203%

Overall 0.00256% 41/1,603,926 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,765
European (non-Finnish)	0.00315%	31,709
South Asian	0.00222%	45,051

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: AOC2
Protein: p.Thr486Met
Coding: c.1457C>T
MANE Select: NM_009590
dbSNP: rs140222638
Type: single nucleotide variant
Location: chr17:42846083 (GRCh38)
Gene constraint: LOEUF 1.292 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.10

Full AOC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AOC2 p.Arg597= Benign ★★ same type
AOC2 p.Pro141Leu Benign ★★ ⚠ same type
AOC2 p.Ala104Thr Uncertain significance ★ ⚠ same type
AOC2 p.Ala218Thr Uncertain significance ★ ⚠ same type
AOC2 p.Ala415Pro Uncertain significance ★ ⚠ same type
AOC2 p.Ala450Val Uncertain significance ★ ⚠ same type
AOC2 p.Ala519Gly Uncertain significance ★ ⚠ same type
AOC2 p.Ala592Thr 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/aoc2-p-thr486met (accessed [today's date]).

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