Is APOL2 p.Arg176Pro (c.527G>C) pathogenic?

APOL2 p.Arg176Pro (c.527G>C) is classified Uncertain significance in APOL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: ambiguous (0.4771); Very rare (popmax 0.00133%, afr).

How common is APOL2 p.Arg176Pro (c.527G>C) in the general population?

APOL2 p.Arg176Pro (c.527G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about APOL2 p.Arg176Pro (c.527G>C)?

AlphaMissense predicts ambiguous (score 0.4771) — an in-silico prediction, not a clinical call.

APOL2 p.Arg176Pro

c.527G>C · VCV3886641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4771	ambiguous
REVEL	0.1	moderately benign-leaning
SaProt	LLR -9.02	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -3
Regional constraint	o/e 1.13	unconstrained · MANE · 5,755 bp · p 0.006 · regional, not allelic
Overall
CADD	0.144	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 0.00133% African / African-American · 1/75,044 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,190 alleles · very rare exomes 3/1,461,878 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,044
European (non-Finnish)	0.000169%	590,019

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.Arg176Pro
Coding: c.527G>C
MANE Select: NM_030882
Type: single nucleotide variant
Location: chr22:36227891 (GRCh38)
Gene constraint: LOEUF 1.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.04 · 1 PDB

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

Similar variants

APOL2 p.Arg176Trp 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-arg176pro (accessed [today's date]).

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