Is APOOL p.Val168Ile (c.502G>A) pathogenic?

APOOL p.Val168Ile (c.502G>A) is classified Likely benign in APOOL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-14). AlphaMissense: likely benign (0.074); Very rare (popmax 0.00667%, nfe).

How common is APOOL p.Val168Ile (c.502G>A) in the general population?

APOOL p.Val168Ile (c.502G>A) is very rare (popmax 0.00667%, nfe) (gnomAD).

What do computational predictors say about APOOL p.Val168Ile (c.502G>A)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

APOOL p.Val168Ile

c.502G>A · rs373265700 · VCV2369032

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.00	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 2	GERP 2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 84 kb · p 0.38 · regional, not allelic
Overall
CADD	0.566	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 0.00667% European (non-Finnish) · 58/869,066 alleles

Filtering AF 0.00523% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00479%

Overall 0.00562% 65/1,157,524 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0239%	4,178
European (non-Finnish)grpmax	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.00438%	22,813

Ashkenazi Jewish 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: APOOL
Protein: p.Val168Ile
Coding: c.502G>A
MANE Select: NM_198450
dbSNP: rs373265700
Type: single nucleotide variant
Location: chrX:85074013 (GRCh38)
Structure: AlphaFold pLDDT 70.83

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

Similar variants

APOOL p.Ala124Glu Uncertain significance ★ ⚠ same type
APOOL p.Ala178Gly Uncertain significance ★ ⚠ same type
APOOL p.Ala241Ser Uncertain significance ★ ⚠ same type
APOOL p.Arg69Cys Uncertain significance ★ ⚠ same type
APOOL p.Arg69His Uncertain significance ★ ⚠ same type
APOOL p.Gln156His Uncertain significance ★ same type
APOOL p.Gln173His Uncertain significance ★ ⚠ same type
APOOL p.Glu30Lys 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/apool-p-val168ile (accessed [today's date]).

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