Is APOL2 p.Leu52Pro (c.155T>C) pathogenic?

APOL2 p.Leu52Pro (c.155T>C) is classified Uncertain significance in APOL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely pathogenic (0.8696); Very rare (popmax 0.00102%, nfe).

How common is APOL2 p.Leu52Pro (c.155T>C) in the general population?

APOL2 p.Leu52Pro (c.155T>C) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about APOL2 p.Leu52Pro (c.155T>C)?

AlphaMissense predicts likely pathogenic (score 0.8696) — an in-silico prediction, not a clinical call.

APOL2 p.Leu52Pro

c.155T>C · VCV3418170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8696	likely pathogenic · top 2% in APOL2
REVEL	0.205	benign-leaning
SaProt	LLR -14.55	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.63, phastCons 0.055
Regional constraint	o/e 1.13	unconstrained · MANE · 5,755 bp · p 0.006 · regional, not allelic
Overall
CADD	21.1	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 0.00102% European (non-Finnish) · 12/1,179,844 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000821% 12/1,461,498 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: APOL2
Protein: p.Leu52Pro
Coding: c.155T>C
MANE Select: NM_030882
Type: single nucleotide variant
Location: chr22:36228263 (GRCh38)
Gene constraint: LOEUF 1.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.04 · 1 PDB
Residue 52: an α-helix

Full APOL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL2 p.Leu52Phe Uncertain significance ★ ⚠ same residue
APOL2 p.Arg53His Uncertain significance ★★ ⚠ same type
APOL2 p.Arg78Lys Benign ★★ same type
APOL2 c.11-1G>C Uncertain significance ★ same type
APOL2 p.Ala179Val Uncertain significance ★ ⚠ same type
APOL2 p.Ala238Thr Uncertain significance ★ ⚠ same type
APOL2 p.Ala240Asp Uncertain significance ★ ⚠ same type
APOL2 p.Ala265Val 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/apol2-p-leu52pro (accessed [today's date]).

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