Is AOAH p.Lys89Thr (c.266A>C) pathogenic?

AOAH p.Lys89Thr (c.266A>C) is classified Uncertain significance in AOAH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.0647); Very rare (popmax 8.49e-05%, nfe).

How common is AOAH p.Lys89Thr (c.266A>C) in the general population?

AOAH p.Lys89Thr (c.266A>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about AOAH p.Lys89Thr (c.266A>C)?

AlphaMissense predicts likely benign (score 0.0647) — an in-silico prediction, not a clinical call.

AOAH p.Lys89Thr

c.266A>C · VCV4641344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0647	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -5.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.03	GERP -4.4
Regional constraint	o/e 0.94	unconstrained · MANE · 211 kb · p 0.14 · regional, not allelic
Overall
CADD	2.352	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 8.49e-05% European (non-Finnish) · 1/1,177,540 alleles

Overall 6.86e-05% 1/1,458,752 alleles · very rare

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: AOAH
Protein: p.Lys89Thr
Coding: c.266A>C
MANE Select: NM_001637
Type: single nucleotide variant
Location: chr7:36673967 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.68 · 2 PDB
Residue 89: a disulfide bond; the saposin b-type domain; an α-helix

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

Similar variants

AOAH p.Ala364Val Uncertain significance ★ ⚠ same type
AOAH p.Ala445Val Uncertain significance ★ ⚠ same type
AOAH p.Ala504Val Uncertain significance ★ ⚠ same type
AOAH p.Ala540Val Uncertain significance ★ ⚠ same type
AOAH p.Arg197Gln Uncertain significance ★ ⚠ same type
AOAH p.Arg202Trp Uncertain significance ★ ⚠ same type
AOAH p.Arg322Cys Uncertain significance ★ ⚠ same type
AOAH p.Arg322Ser 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/aoah-p-lys89thr (accessed [today's date]).

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