Is APOL3 p.Arg324Cys (c.970C>T) pathogenic?

APOL3 p.Arg324Cys (c.970C>T) is classified Uncertain significance in APOL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1702); Ultra-rare (popmax 0.0227%, afr).

How common is APOL3 p.Arg324Cys (c.970C>T) in the general population?

APOL3 p.Arg324Cys (c.970C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about APOL3 p.Arg324Cys (c.970C>T)?

AlphaMissense predicts likely benign (score 0.1702) — an in-silico prediction, not a clinical call.

APOL3 p.Arg324Cys

c.970C>T · VCV4641772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1702	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -4.43	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 -20
Overall
CADD	1.026	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R395C vs ClinVar R324C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/74,970 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00211% 34/1,613,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,410
South Asian	0.00988%	10,118
East Asian	0.00446%	22,436
Admixed American	0.00167%	60,010
European (non-Finnish)	0.000424%	235,968

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: APOL3
Protein: p.Arg324Cys
Coding: c.970C>T
MANE Select: NM_145639
Type: single nucleotide variant
Location: chr22:36141226 (GRCh38)
Gene constraint: LOEUF 1.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.87

Full APOL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL3 p.Arg324Leu Uncertain significance ★ ⚠ same residue
APOL3 p.Arg324His Likely benign ★ same residue
APOL3 p.Arg324Ser Likely benign ★ same residue
APOL3 c.-100A>G Benign ★★ same type
APOL3 p.Ala157Thr Benign ★★ same type
APOL3 p.Ala64Val Benign ★★ same type
APOL3 p.Asn31Asp Benign ★★ same type
APOL3 p.Cys13Trp Likely benign ★★ 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/apol3-p-arg324cys (accessed [today's date]).

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