Is APOL6 p.Ala166Pro (c.496G>C) pathogenic?

APOL6 p.Ala166Pro (c.496G>C) is classified Uncertain significance in APOL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely benign (0.3003); Very rare (popmax 0.00127%, nfe).

How common is APOL6 p.Ala166Pro (c.496G>C) in the general population?

APOL6 p.Ala166Pro (c.496G>C) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about APOL6 p.Ala166Pro (c.496G>C)?

AlphaMissense predicts likely benign (score 0.3003) — an in-silico prediction, not a clinical call.

APOL6 p.Ala166Pro

c.496G>C · rs761950647 · VCV3128051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3003 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3003	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -8.34	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 -0.3	GERP -3.5
Regional constraint	o/e 1.02	unconstrained · MANE · 3,167 bp · p 0.67 · regional, not allelic
Overall
CADD	9.714	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 0.00127% European (non-Finnish) · 15/1,180,034 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,613,858 alleles · very rare

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: APOL6
Protein: p.Ala166Pro
Coding: c.496G>C
MANE Select: NM_030641
dbSNP: rs761950647
Type: single nucleotide variant
Location: chr22:35659060 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 54.86

Full APOL6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOL6 p.Ala161Val Uncertain significance ★ ⚠ same type
APOL6 p.Ala181Asp Uncertain significance ★ ⚠ same type
APOL6 p.Ala200Val Uncertain significance ★ ⚠ same type
APOL6 p.Ala263Thr Uncertain significance ★ ⚠ same type
APOL6 p.Ala275Asp Uncertain significance ★ ⚠ same type
APOL6 p.Ala300Ser Uncertain significance ★ ⚠ same type
APOL6 p.Ala5Val Uncertain significance ★ ⚠ same type
APOL6 p.Ala97Asp 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/apol6-p-ala166pro (accessed [today's date]).

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