Is APOL1 p.Arg8Lys (c.23G>A) pathogenic?

APOL1 p.Arg8Lys (c.23G>A) is classified Uncertain significance in APOL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely benign (0.2258); Rare (popmax 0.239%, afr).

How common is APOL1 p.Arg8Lys (c.23G>A) in the general population?

APOL1 p.Arg8Lys (c.23G>A) is rare (popmax 0.239%, afr) (gnomAD).

What do computational predictors say about APOL1 p.Arg8Lys (c.23G>A)?

AlphaMissense predicts likely benign (score 0.2258) — an in-silico prediction, not a clinical call.

APOL1 p.Arg8Lys

c.23G>A · rs769299217 · VCV1432755

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2258 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.239%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2258	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -7.39	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 -0.27	GERP -1.8
Regional constraint	o/e 1.08	unconstrained · MANE · 11 kb · p 0.093 · regional, not allelic
Overall
CADD	5.928	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 0.239% African / African-American · 176/73,662 alleles

Filtering AF 0.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.199%

Overall 0.0125% 202/1,610,268 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.239%	419
Remaining individualsnot grpmax-eligible	0.0145%	6,913
Admixed American	0.01%	9,984
East Asian	0.00224%	44,680
European (non-Finnish)	0.000849%	117,834

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: APOL1
Protein: p.Arg8Lys
Coding: c.23G>A
MANE Select: NM_003661
dbSNP: rs769299217
Type: single nucleotide variant
Location: chr22:36254978 (GRCh38)
Gene constraint: LOEUF 1.68 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.94 · 5 PDB

Full APOL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL1 p.Ala108Glu Uncertain significance ★★ ⚠ same type
APOL1 p.Ala394Gly Uncertain significance ★★ ⚠ same type
APOL1 p.Arg112Cys Uncertain significance ★★ ⚠ same type
APOL1 p.Asp46Gly Uncertain significance ★★ ⚠ same type
APOL1 p.Gln396Ter Uncertain significance ★★ same type
APOL1 p.Glu110Asp Uncertain significance ★★ ⚠ same type
APOL1 p.Glu323Gln Uncertain significance ★★ ⚠ same type
APOL1 p.His298Arg 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/apol1-p-arg8lys (accessed [today's date]).

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