Is APOL1 p.Arg105Ser (c.315G>C) pathogenic?

APOL1 p.Arg105Ser (c.315G>C) is classified Uncertain significance in APOL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: ambiguous (0.4996); Very rare (popmax 0.00195%, nfe).

How common is APOL1 p.Arg105Ser (c.315G>C) in the general population?

APOL1 p.Arg105Ser (c.315G>C) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about APOL1 p.Arg105Ser (c.315G>C)?

AlphaMissense predicts ambiguous (score 0.4996) — an in-silico prediction, not a clinical call.

APOL1 p.Arg105Ser

c.315G>C · rs374427859 · VCV2350926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4996	ambiguous · top 10% in APOL1
REVEL	0.163	moderately benign-leaning
SaProt	LLR -5.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -1.5
Regional constraint	o/e 1.08	unconstrained · MANE · 11 kb · p 0.093 · regional, not allelic
Overall
CADD	14.83	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,990 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00192% 31/1,613,828 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Finnishnot grpmax-eligible	0.00469%	21,326
European (non-Finnish)grpmax	0.00195%	51,304
African / African-American	0.00134%	74,884

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.Arg105Ser
Coding: c.315G>C
MANE Select: NM_003661
dbSNP: rs374427859
Type: single nucleotide variant
Location: chr22:36265151 (GRCh38)
Gene constraint: LOEUF 1.68 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.94 · 5 PDB
Residue 105: the 'pore-forming region' region; an α-helix

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-arg105ser (accessed [today's date]).

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