Is APOL2 p.Arg100His (c.299G>A) pathogenic?

APOL2 p.Arg100His (c.299G>A) is classified Uncertain significance in APOL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). AlphaMissense: likely benign (0.0822); Very rare (popmax 0.00891%, eas).

How common is APOL2 p.Arg100His (c.299G>A) in the general population?

APOL2 p.Arg100His (c.299G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about APOL2 p.Arg100His (c.299G>A)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

APOL2 p.Arg100His

c.299G>A · VCV3308592

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -7.39	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 -3.4
Regional constraint	o/e 1.13	unconstrained · MANE · 5,755 bp · p 0.006 · regional, not allelic
Overall
CADD	0.007	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 0.00891% East Asian · 4/44,892 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000434% 7/1,614,108 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,223
Admixed American	0.00167%	60,008
South Asian	0.0011%	91,092
European (non-Finnish)	8.47e-05%	1,180,048

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.Arg100His
Coding: c.299G>A
MANE Select: NM_030882
Type: single nucleotide variant
Location: chr22:36228119 (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.Arg100Cys Uncertain significance ★ ⚠ same residue
APOL2 p.Arg100Gly 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

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-arg100his (accessed [today's date]).

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