Is APOL1 p.Ser65= (c.195T>C) pathogenic?

APOL1 p.Ser65= (c.195T>C) is classified Likely benign in APOL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-30). Ultra-rare (popmax 0.017%, nfe).

How common is APOL1 p.Ser65= (c.195T>C) in the general population?

APOL1 p.Ser65= (c.195T>C) is ultra-rare (popmax 0.017%, nfe) (gnomAD).

APOL1 p.Ser65=

c.195T>C · rs201153239 · VCV2721347

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.023	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.9	GERP -2.1
Overall
CADD	0.591	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.017% European (non-Finnish) · 201/1,179,358 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0141% 227/1,613,216 alleles · ultra-rare exomes 211/1,461,044 · genomes 16/152,172 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.032%	3,123
European (non-Finnish)grpmax	0.017%	5,867
African / African-American	0.00534%	18,724
Finnishnot grpmax-eligible	0.00156%	63,996
South Asian	0.0011%	91,066

Remaining individuals 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: APOL1
Protein: p.Ser65=
Coding: c.195T>C
MANE Select: NM_003661
dbSNP: rs201153239
Type: single nucleotide variant
Location: chr22:36261603 (GRCh38)
Gene constraint: LOEUF 1.68 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.94 · 5 PDB
Residue 65: the 'pore-forming region' region

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-ser65 (accessed [today's date]).

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