Is APOL3 p.Arg324Ser (c.970C>A) pathogenic?

APOL3 p.Arg324Ser (c.970C>A) is classified Likely benign in APOL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.2067); Ultra-rare (popmax 0.0223%, eas).

How common is APOL3 p.Arg324Ser (c.970C>A) in the general population?

APOL3 p.Arg324Ser (c.970C>A) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about APOL3 p.Arg324Ser (c.970C>A)?

AlphaMissense predicts likely benign (score 0.2067) — an in-silico prediction, not a clinical call.

APOL3 p.Arg324Ser

c.970C>A · VCV3935068

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2067 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2067	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -2.98	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 -20
Overall
CADD	0.008	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R395S vs ClinVar R324S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,884 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.000744% 12/1,613,708 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,488
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	8.48e-05%	1,179,846

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.Arg324Ser
Coding: c.970C>A
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.Arg324Cys Uncertain significance ★ ⚠ same residue
APOL3 p.Arg324Leu Uncertain significance ★ ⚠ same residue
APOL3 p.Arg324His 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-arg324ser (accessed [today's date]).

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