Is AOC3 p.Val431Met (c.1291G>A) pathogenic?

AOC3 p.Val431Met (c.1291G>A) is classified Uncertain significance in AOC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely benign (0.2628); Ultra-rare (popmax 0.0346%, afr).

How common is AOC3 p.Val431Met (c.1291G>A) in the general population?

AOC3 p.Val431Met (c.1291G>A) is ultra-rare (popmax 0.0346%, afr) (gnomAD).

What do computational predictors say about AOC3 p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely benign (score 0.2628) — an in-silico prediction, not a clinical call.

AOC3 p.Val431Met

c.1291G>A · VCV3921641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2628 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0346%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2628	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -10.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.1	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 5,203 bp · p 8.7e-06 · regional, not allelic
Overall
CADD	25.8	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 0.0346% African / African-American · 26/75,038 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00446% 72/1,614,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.056%	1,786
African / African-Americangrpmax	0.0346%	2,886
Middle Eastern	0.0165%	6,062
South Asian	0.0011%	91,088
European (non-Finnish)	0.000763%	131,117

Remaining individuals 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: AOC3
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_003734
Type: single nucleotide variant
Location: chr17:42852634 (GRCh38)
Gene constraint: LOEUF 1.056 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.15 · 11 PDB
Residue 431: 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-val431met (accessed [today's date]).

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