Is APOL3 p.Arg306Trp (c.916C>T) pathogenic?

APOL3 p.Arg306Trp (c.916C>T) is classified Uncertain significance in APOL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-07). AlphaMissense: likely benign (0.1702); Rare (popmax 0.181%, mid).

How common is APOL3 p.Arg306Trp (c.916C>T) in the general population?

APOL3 p.Arg306Trp (c.916C>T) is rare (popmax 0.181%, mid) (gnomAD).

What do computational predictors say about APOL3 p.Arg306Trp (c.916C>T)?

AlphaMissense predicts likely benign (score 0.1702) — an in-silico prediction, not a clinical call.

APOL3 p.Arg306Trp

c.916C>T · rs371643988 · VCV3128027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1702 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.181%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1702	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -11.66	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15
Overall
CADD	14.08	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R377W vs ClinVar R306W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.181% Middle Eastern · 11/6,062 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0787%

Overall 0.0132% 213/1,614,100 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.181%	551
East Asian	0.029%	3,452
Finnishnot grpmax-eligible	0.0172%	5,820
Remaining individualsnot grpmax-eligible	0.016%	6,251
European (non-Finnish)	0.0134%	7,468
South Asian	0.00659%	15,180
African / African-American	0.00533%	18,750

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: APOL3
Protein: p.Arg306Trp
Coding: c.916C>T
MANE Select: NM_145639
dbSNP: rs371643988
Type: single nucleotide variant
Location: chr22:36141280 (GRCh38)
Gene constraint: LOEUF 1.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.87

Full APOL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL3 c.-100A>G Benign ★★ same type
APOL3 p.Ala157Thr Benign ★★ same type
APOL3 p.Ala64Val Benign ★★ same type
APOL3 p.Asn31Asp Benign ★★ same type
APOL3 p.Cys13Trp Likely benign ★★ same type
APOL3 p.Cys22= Benign ★★ same type
APOL3 p.Gly35Val Likely benign ★★ same type
APOL3 p.Thr149Ile Benign ★★ ⚠ 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/apol3-p-arg306trp (accessed [today's date]).

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