Is APOL3 p.Cys22= (c.66C>T) pathogenic?

APOL3 p.Cys22= (c.66C>T) is classified Benign in APOL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Very rare (popmax 0.00212%, nfe).

How common is APOL3 p.Cys22= (c.66C>T) in the general population?

APOL3 p.Cys22= (c.66C>T) is very rare (popmax 0.00212%, nfe) (gnomAD).

APOL3 p.Cys22=

c.66C>T · rs145828103 · VCV764006

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7
Overall
CADD	0.108	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 25/1,177,546 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.0115% 186/1,611,314 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.483%	207
Remaining individualsnot grpmax-eligible	0.0289%	3,463
European (non-Finnish)grpmax	0.00212%	47,102

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: APOL3
Protein: p.Cys22=
Coding: c.66C>T
MANE Select: NM_145639 · reported on NM_145640
dbSNP: rs145828103
Type: single nucleotide variant
Location: chr22:36160826 (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 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
APOL3 p.Gly35Val Likely benign ★★ same type
APOL3 p.Thr149Ile Benign ★★ ⚠ same type
APOL3 c.-112C>T 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/apol3-p-cys22 (accessed [today's date]).

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