Is AOC2 p.Tyr446Cys (c.1337A>G) pathogenic?

AOC2 p.Tyr446Cys (c.1337A>G) is classified Uncertain significance in AOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-03). AlphaMissense: ambiguous (0.3493); Very rare (popmax 0.00401%, afr).

How common is AOC2 p.Tyr446Cys (c.1337A>G) in the general population?

AOC2 p.Tyr446Cys (c.1337A>G) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about AOC2 p.Tyr446Cys (c.1337A>G)?

AlphaMissense predicts ambiguous (score 0.3493) — an in-silico prediction, not a clinical call.

AOC2 p.Tyr446Cys

c.1337A>G · rs374369571 · VCV3127361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3493 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3493	ambiguous
REVEL	0.262	benign-leaning
SaProt	LLR -13.12	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.66	GERP -4.2, phastCons 0.005
Regional constraint	o/e 1.05	unconstrained · MANE · 5,718 bp · p 0.1 · regional, not allelic
Overall
CADD	18.23	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 0.00401% African / African-American · 3/74,880 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00458% 74/1,613,996 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0515%	1,940
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-Americangrpmax	0.00401%	24,960
Admixed American	0.00333%	29,999
European (non-Finnish)	0.00263%	38,066
South Asian	0.0011%	91,080

Finnish 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: AOC2
Protein: p.Tyr446Cys
Coding: c.1337A>G
MANE Select: NM_009590
dbSNP: rs374369571
Type: single nucleotide variant
Location: chr17:42845963 (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.Tyr446Ser Uncertain significance ★ ⚠ same residue
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

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-tyr446cys (accessed [today's date]).

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