Is AOC2 p.Arg581Cys (c.1741C>T) pathogenic?

AOC2 p.Arg581Cys (c.1741C>T) is classified Uncertain significance in AOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.135); Ultra-rare (popmax 0.034%, sas).

How common is AOC2 p.Arg581Cys (c.1741C>T) in the general population?

AOC2 p.Arg581Cys (c.1741C>T) is ultra-rare (popmax 0.034%, sas) (gnomAD).

What do computational predictors say about AOC2 p.Arg581Cys (c.1741C>T)?

AlphaMissense predicts likely benign (score 0.135) — an in-silico prediction, not a clinical call.

AOC2 p.Arg581Cys

c.1741C>T · rs143262935 · VCV3127366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.135 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.135	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -13.19	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 2.1, phastCons 0.59
Regional constraint	o/e 1.05	unconstrained · MANE · 5,718 bp · p 0.1 · regional, not allelic
Overall
CADD	27.3	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 0.034% South Asian · 31/91,088 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00266% 43/1,614,218 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.034%	2,938
East Asian	0.00446%	22,443
African / African-American	0.004%	25,017
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000508%	196,673

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.Arg581Cys
Coding: c.1741C>T
MANE Select: NM_009590
dbSNP: rs143262935
Type: single nucleotide variant
Location: chr17:42849238 (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.Arg581Pro 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-arg581cys (accessed [today's date]).

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