Is APOO p.Thr18Ile (c.53C>T) pathogenic?

APOO p.Thr18Ile (c.53C>T) is classified Uncertain significance in APOO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: ambiguous (0.4131); Very rare (popmax 9.28e-05%).

How common is APOO p.Thr18Ile (c.53C>T) in the general population?

APOO p.Thr18Ile (c.53C>T) is very rare (popmax 9.28e-05%) (gnomAD).

What do computational predictors say about APOO p.Thr18Ile (c.53C>T)?

AlphaMissense predicts ambiguous (score 0.4131) — an in-silico prediction, not a clinical call.

APOO p.Thr18Ile

c.53C>T · VCV4641803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4131 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.28e-05%)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4131	ambiguous
REVEL	0.183	benign-leaning
SaProt	LLR -6.98	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 67 kb · p 0.15 · regional, not allelic
Overall
CADD	23.2	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 9.28e-05%

Overall 9.28e-05% 1/1,077,533 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: APOO
Protein: p.Thr18Ile
Coding: c.53C>T
MANE Select: NM_024122
Type: single nucleotide variant
Location: chrX:23880909 (GRCh38)
Structure: AlphaFold pLDDT 74.34

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

Similar variants

APOO c.117+16T>C Benign ★★ same type
APOO p.Leu166Val Benign ★★ same type
APOO p.Ile117Thr Pathogenic ★ ⚠ same type
APOO p.Ala12Gly Uncertain significance ★ ⚠ same type
APOO p.Asp98Glu Uncertain significance ★ ⚠ same type
APOO p.Glu72Lys Uncertain significance ★ ⚠ same type
APOO p.Gly163Ala Uncertain significance ★ ⚠ same type
APOO p.Gly173Glu 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/apoo-p-thr18ile (accessed [today's date]).

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