Is AOC1 p.Pro280Ser (c.838C>T) pathogenic?

AOC1 p.Pro280Ser (c.838C>T) is classified Uncertain significance in AOC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.0772); Ultra-rare (popmax 0.0952%, afr).

How common is AOC1 p.Pro280Ser (c.838C>T) in the general population?

AOC1 p.Pro280Ser (c.838C>T) is ultra-rare (popmax 0.0952%, afr) (gnomAD).

What do computational predictors say about AOC1 p.Pro280Ser (c.838C>T)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

AOC1 p.Pro280Ser

c.838C>T · rs370340838 · VCV2412464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0952%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.31	GERP -2
Regional constraint	o/e 0.91	unconstrained · MANE · 4,735 bp · p 0.0054 · regional, not allelic
Overall
CADD	12.82	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 0.0952% African / African-American · 71/74,550 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0709%

Overall 0.0052% 83/1,596,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0952%	1,050
Admixed American	0.012%	8,354
Remaining individualsnot grpmax-eligible	0.0065%	15,392
European (non-Finnish)	8.55e-05%	1,170,168

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: AOC1
Protein: p.Pro280Ser
Coding: c.838C>T
MANE Select: NM_001091
dbSNP: rs370340838
Type: single nucleotide variant
Location: chr7:150857308 (GRCh38)
Gene constraint: LOEUF 1.253 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 5 PDB
Residue 280: an α-helix

Full AOC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AOC1 p.Asn659His Benign ★★ same type
AOC1 p.Ala347Val Uncertain significance ★ ⚠ same type
AOC1 p.Ala357Val Uncertain significance ★ ⚠ same type
AOC1 p.Ala487Thr Uncertain significance ★ ⚠ same type
AOC1 p.Ala565Val Uncertain significance ★ ⚠ same type
AOC1 p.Ala614Thr Uncertain significance ★ ⚠ same type
AOC1 p.Arg180Gly Uncertain significance ★ ⚠ same type
AOC1 p.Arg190Leu 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/aoc1-p-pro280ser (accessed [today's date]).

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