Is APOOL p.Arg69Cys (c.205C>T) pathogenic?

APOOL p.Arg69Cys (c.205C>T) is classified Uncertain significance in APOOL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.1741); Ultra-rare (popmax 0.0175%, afr).

How common is APOOL p.Arg69Cys (c.205C>T) in the general population?

APOOL p.Arg69Cys (c.205C>T) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

What do computational predictors say about APOOL p.Arg69Cys (c.205C>T)?

AlphaMissense predicts likely benign (score 0.1741) — an in-silico prediction, not a clinical call.

APOOL p.Arg69Cys

c.205C>T · VCV4641805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1741 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1741	likely benign
REVEL	0.54	indeterminate
SaProt	LLR -12.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 84 kb · p 0.38 · regional, not allelic
Overall
CADD	21.9	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 0.0175% African / African-American · 10/57,094 alleles

Filtering AF 0.00942% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00248% 30/1,209,220 alleles · ultra-rare exomes 22/1,097,542 · genomes 8/111,678 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,709
Remaining individualsnot grpmax-eligible	0.00631%	15,850
East Asian	0.00592%	16,879
Admixed American	0.00219%	45,614
European (non-Finnish)	0.00156%	63,913

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.Arg69Cys
Coding: c.205C>T
MANE Select: NM_198450
Type: single nucleotide variant
Location: chrX:85051473 (GRCh38)
Structure: AlphaFold pLDDT 70.83

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

Similar variants

APOOL p.Arg69His Uncertain significance ★ ⚠ same residue
APOOL p.Ala124Glu Uncertain significance ★ ⚠ same type
APOOL p.Ala178Gly Uncertain significance ★ ⚠ same type
APOOL p.Ala241Ser 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
APOOL p.Glu56Ala 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-arg69cys (accessed [today's date]).

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