Is APOL6 p.Ala275Asp (c.824C>A) pathogenic?

APOL6 p.Ala275Asp (c.824C>A) is classified Uncertain significance in APOL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: ambiguous (0.5114); Ultra-rare (popmax 0.0713%, eas).

How common is APOL6 p.Ala275Asp (c.824C>A) in the general population?

APOL6 p.Ala275Asp (c.824C>A) is ultra-rare (popmax 0.0713%, eas) (gnomAD).

What do computational predictors say about APOL6 p.Ala275Asp (c.824C>A)?

AlphaMissense predicts ambiguous (score 0.5114) — an in-silico prediction, not a clinical call.

APOL6 p.Ala275Asp

c.824C>A · VCV3418308

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5114 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0713%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5114	ambiguous · top 10% in APOL6
REVEL	0.253	benign-leaning
SaProt	LLR -13.50	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.78, phastCons 0.96
Regional constraint	o/e 1.02	unconstrained · MANE · 3,167 bp · p 0.67 · regional, not allelic
Overall
CADD	22.8	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 0.0713% East Asian · 32/44,884 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0452%

Overall 0.00279% 45/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0713%	1,403
Remaining individualsnot grpmax-eligible	0.0128%	7,810
South Asian	0.00549%	18,216

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.Ala275Asp
Coding: c.824C>A
MANE Select: NM_030641
Type: single nucleotide variant
Location: chr22:35659388 (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.Ala166Pro 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.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-ala275asp (accessed [today's date]).

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