Is APOL2 p.Asp74Glu (c.222C>G) pathogenic?

APOL2 p.Asp74Glu (c.222C>G) is classified Uncertain significance in APOL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-17). AlphaMissense: likely benign (0.2177); Ultra-rare (popmax 0.0955%, sas).

How common is APOL2 p.Asp74Glu (c.222C>G) in the general population?

APOL2 p.Asp74Glu (c.222C>G) is ultra-rare (popmax 0.0955%, sas) (gnomAD).

What do computational predictors say about APOL2 p.Asp74Glu (c.222C>G)?

AlphaMissense predicts likely benign (score 0.2177) — an in-silico prediction, not a clinical call.

APOL2 p.Asp74Glu

c.222C>G · rs201164781 · VCV3128021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2177 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0955%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2177	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -5.78	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 -20	GERP -3.1
Regional constraint	o/e 1.13	unconstrained · MANE · 5,755 bp · p 0.006 · regional, not allelic
Overall
CADD	0.091	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 0.0955% South Asian · 87/91,086 alleles

Filtering AF 0.0793% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0733%

Overall 0.0574% 926/1,614,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0955%	1,047
European (non-Finnish)	0.0658%	1,521
Remaining individualsnot grpmax-eligible	0.0448%	2,233
Finnishnot grpmax-eligible	0.0344%	2,910
Middle Eastern	0.0165%	6,062
African / African-American	0.0107%	9,381
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
Admixed American	0.00333%	30,012

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.Asp74Glu
Coding: c.222C>G
MANE Select: NM_030882
dbSNP: rs201164781
Type: single nucleotide variant
Location: chr22:36228196 (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-asp74glu (accessed [today's date]).

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