Is APOL5 p.Pro428Leu (c.1283C>T) pathogenic?

APOL5 p.Pro428Leu (c.1283C>T) is classified Uncertain significance in APOL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-11). AlphaMissense: likely benign (0.1207); Very rare (popmax 0.00646%, nfe).

How common is APOL5 p.Pro428Leu (c.1283C>T) in the general population?

APOL5 p.Pro428Leu (c.1283C>T) is very rare (popmax 0.00646%, nfe) (gnomAD).

What do computational predictors say about APOL5 p.Pro428Leu (c.1283C>T)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

APOL5 p.Pro428Leu

c.1283C>T · VCV3418249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00646%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.91	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 0.014	GERP -1.4
Regional constraint	o/e 1.04	unconstrained · MANE · 2,069 bp · p 0.56 · regional, not allelic
Overall
CADD	15.69	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 0.00646% European (non-Finnish) · 76/1,175,876 alleles

Filtering AF 0.00529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00517% 83/1,604,150 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00646%	15,472
Admixed American	0.00515%	19,433
Remaining individualsnot grpmax-eligible	0.00483%	20,694
South Asian	0.00112%	89,320

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: APOL5
Protein: p.Pro428Leu
Coding: c.1283C>T
MANE Select: NM_030642
Type: single nucleotide variant
Location: chr22:35728879 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 41.66
Residue 428: the 'disordered' region

Full APOL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL5 p.Glu81Lys Benign ★★ same type
APOL5 p.Ala124Glu Uncertain significance ★ ⚠ same type
APOL5 p.Ala141Asp Uncertain significance ★ ⚠ same type
APOL5 p.Ala146Asp Uncertain significance ★ ⚠ same type
APOL5 p.Ala163Glu Uncertain significance ★ ⚠ same type
APOL5 p.Ala197Ser Uncertain significance ★ ⚠ same type
APOL5 p.Ala198Gly Uncertain significance ★ ⚠ same type
APOL5 p.Ala226Thr 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/apol5-p-pro428leu (accessed [today's date]).

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