Is APOL1 p.Ser40Ile (c.119G>T) pathogenic?

APOL1 p.Ser40Ile (c.119G>T) is classified Uncertain significance in APOL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely benign (0.1346); Very rare (popmax 0.00153%, nfe).

How common is APOL1 p.Ser40Ile (c.119G>T) in the general population?

APOL1 p.Ser40Ile (c.119G>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about APOL1 p.Ser40Ile (c.119G>T)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

APOL1 p.Ser40Ile

c.119G>T · rs1412411332 · VCV3128017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -8.30	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 -3.1	GERP -2
Regional constraint	o/e 1.08	unconstrained · MANE · 11 kb · p 0.093 · regional, not allelic
Overall
CADD	0.209	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,180,020 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00123% 18/1,461,882 alleles · very rare

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.Ser40Ile
Coding: c.119G>T
MANE Select: NM_003661
dbSNP: rs1412411332
Type: single nucleotide variant
Location: chr22:36257339 (GRCh38)
Gene constraint: LOEUF 1.68 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.94 · 5 PDB
Residue 40: the 'disordered' 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-ser40ile (accessed [today's date]).

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