Is AOC1 p.Phe326Val (c.976T>G) pathogenic?

AOC1 p.Phe326Val (c.976T>G) is classified Uncertain significance in AOC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: ambiguous (0.3768); Very rare (popmax 0.00602%, nfe).

How common is AOC1 p.Phe326Val (c.976T>G) in the general population?

AOC1 p.Phe326Val (c.976T>G) is very rare (popmax 0.00602%, nfe) (gnomAD).

What do computational predictors say about AOC1 p.Phe326Val (c.976T>G)?

AlphaMissense predicts ambiguous (score 0.3768) — an in-silico prediction, not a clinical call.

AOC1 p.Phe326Val

c.976T>G · VCV3876193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00602%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3768	ambiguous
REVEL	0.189	benign-leaning
SaProt	LLR -5.76	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.91, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 4,735 bp · p 0.0054 · regional, not allelic
Overall
CADD	21.6	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 0.00602% European (non-Finnish) · 71/1,179,602 alleles

Filtering AF 0.00486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00447%

Overall 0.00465% 75/1,611,480 alleles · very rare exomes 68/1,459,150 · genomes 7/152,330 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00602%	16,614
African / African-American	0.00266%	37,529
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,440

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.Phe326Val
Coding: c.976T>G
MANE Select: NM_001091
Type: single nucleotide variant
Location: chr7:150857446 (GRCh38)
Gene constraint: LOEUF 1.253 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 5 PDB
Residue 326: a β-strand

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-phe326val (accessed [today's date]).

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