Is APOL2 p.Ala159Thr (c.475G>A) pathogenic?

APOL2 p.Ala159Thr (c.475G>A) is classified Likely benign in APOL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-30). AlphaMissense: likely benign (0.1741); Rare (popmax 0.146%, sas).

How common is APOL2 p.Ala159Thr (c.475G>A) in the general population?

APOL2 p.Ala159Thr (c.475G>A) is rare (popmax 0.146%, sas) (gnomAD).

What do computational predictors say about APOL2 p.Ala159Thr (c.475G>A)?

AlphaMissense predicts likely benign (score 0.1741) — an in-silico prediction, not a clinical call.

APOL2 p.Ala159Thr

c.475G>A · VCV4688483

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1741 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.146%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1741	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -8.97	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 -7.3	GERP -3.4
Regional constraint	o/e 1.13	unconstrained · MANE · 5,755 bp · p 0.006 · regional, not allelic
Overall
CADD	1.998	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 0.146% South Asian · 133/91,092 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.00917% 148/1,614,228 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.146%	685
Remaining individualsnot grpmax-eligible	0.0192%	5,209
African / African-American	0.004%	25,019

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.Ala159Thr
Coding: c.475G>A
MANE Select: NM_030882
Type: single nucleotide variant
Location: chr22:36227943 (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.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
APOL2 p.Ala314Val 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-ala159thr (accessed [today's date]).

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