Is AOC2 p.His604Pro (c.1811A>C) pathogenic?

AOC2 p.His604Pro (c.1811A>C) is classified Uncertain significance in AOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely benign (0.1064); Ultra-rare (popmax 0.025%, nfe).

How common is AOC2 p.His604Pro (c.1811A>C) in the general population?

AOC2 p.His604Pro (c.1811A>C) is ultra-rare (popmax 0.025%, nfe) (gnomAD).

What do computational predictors say about AOC2 p.His604Pro (c.1811A>C)?

AlphaMissense predicts likely benign (score 0.1064) — an in-silico prediction, not a clinical call.

AOC2 p.His604Pro

c.1811A>C · rs201540930 · VCV2343343

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1064	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.1	GERP -1.5, phastCons 0.66
Regional constraint	o/e 1.05	unconstrained · MANE · 5,718 bp · p 0.1 · regional, not allelic
Overall
CADD	18.34	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% European (non-Finnish) · 295/1,180,038 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.0201% 324/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.025%	4,000
Remaining individualsnot grpmax-eligible	0.0192%	5,207
Admixed American	0.0133%	7,500
Finnishnot grpmax-eligible	0.00625%	16,008
African / African-American	0.00534%	18,732
South Asian	0.0011%	91,082

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.His604Pro
Coding: c.1811A>C
MANE Select: NM_009590
dbSNP: rs201540930
Type: single nucleotide variant
Location: chr17:42849308 (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-his604pro (accessed [today's date]).

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