Is APOO p.Leu166Val (c.496T>G) pathogenic?

APOO p.Leu166Val (c.496T>G) is classified Benign in APOO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-02-25). AlphaMissense: likely benign (0.1199); Common (popmax 6.96%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about APOO p.Leu166Val (c.496T>G)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

APOO p.Leu166Val

Q: How common is APOO p.Leu166Val (c.496T>G) in the general population?

APOO p.Leu166Val (c.496T>G) is common (popmax 6.96%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.496T>G · rs75916244 · VCV780687

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.96%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -5.98	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 3.6	GERP -0.18, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 67 kb · p 0.15 · regional, not allelic
Overall
CADD	19.28	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 6.96% African / African-American · 3,964/56,949 alleles

Filtering AF 6.78% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.71%

Overall 0.376% 4,530/1,205,637 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.96%	14
Admixed American	0.559%	179
Remaining individualsnot grpmax-eligible	0.522%	191
Middle Eastern	0.207%	482
South Asian	0.0106%	9,436
European (non-Finnish)	0.00549%	18,209

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.Leu166Val
Coding: c.496T>G
MANE Select: NM_024122
dbSNP: rs75916244
Type: single nucleotide variant
Location: chrX:23856367 (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.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
APOO p.Ile133Met 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-leu166val (accessed [today's date]).

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