Is AOC3 p.Ser466Pro (c.1396T>C) pathogenic?

AOC3 p.Ser466Pro (c.1396T>C) is classified Uncertain significance in AOC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: ambiguous (0.5628); Very rare (popmax 0.004%, afr).

How common is AOC3 p.Ser466Pro (c.1396T>C) in the general population?

AOC3 p.Ser466Pro (c.1396T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about AOC3 p.Ser466Pro (c.1396T>C)?

AlphaMissense predicts ambiguous (score 0.5628) — an in-silico prediction, not a clinical call.

AOC3 p.Ser466Pro

c.1396T>C · VCV3921650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5628	ambiguous
REVEL	0.148	moderately benign-leaning
SaProt	LLR -11.21	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 1.6	GERP -0.18, phastCons 0.98
Regional constraint	o/e 0.86	unconstrained · MANE · 5,203 bp · p 8.7e-06 · regional, not allelic
Overall
CADD	22.3	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 0.004% African / African-American · 3/74,930 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00204% 33/1,614,120 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,977
European (non-Finnish)	0.00237%	42,145
East Asian	0.00223%	44,896
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: AOC3
Protein: p.Ser466Pro
Coding: c.1396T>C
MANE Select: NM_003734
Type: single nucleotide variant
Location: chr17:42852739 (GRCh38)
Gene constraint: LOEUF 1.056 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.15 · 11 PDB
Residue 466: a β-strand

Full AOC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AOC3 p.Arg73Cys Uncertain significance ★★ ⚠ same type
AOC3 p.Ala582Thr Benign ★★ same type
AOC3 p.Arg329Gln Benign/Likely benign ★★ same type
AOC3 p.Arg441Trp Benign ★★ ⚠ same type
AOC3 p.Arg566Gln Likely benign ★★ same type
AOC3 p.Ile371Thr Benign ★★ same type
AOC3 p.Tyr271= Likely benign ★★ same type
AOC3 p.Tyr406Asn Benign ★★ ⚠ 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/aoc3-p-ser466pro (accessed [today's date]).

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