Is AKAP9 p.Arg2016Cys (c.6046C>T) pathogenic?

AKAP9 p.Arg2016Cys (c.6046C>T) is classified Conflicting classifications of pathogenicity in AKAP9 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.1168); Ultra-rare (popmax 0.0717%, amr); Associated with long QT syndrome.

What condition is associated with AKAP9 p.Arg2016Cys (c.6046C>T)?

AKAP9 p.Arg2016Cys (c.6046C>T) is associated with long QT syndrome, cardiomyopathy (ClinVar).

How common is AKAP9 p.Arg2016Cys (c.6046C>T) in the general population?

AKAP9 p.Arg2016Cys (c.6046C>T) is ultra-rare (popmax 0.0717%, amr) (gnomAD).

What do computational predictors say about AKAP9 p.Arg2016Cys (c.6046C>T)?

AlphaMissense predicts likely benign (score 0.1168) — an in-silico prediction, not a clinical call.

AKAP9 p.Arg2016Cys

c.6046C>T · rs376950905 · VCV417028

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1168 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0717%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.1168	likely benign
REVEL	0.039	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.52	GERP 1.2
Regional constraint	o/e 0.97	unconstrained · MANE · 130 kb · p 0.16 · regional, not allelic
Overall
CADD	17.98	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 0.0717% Admixed American · 43/59,950 alleles

Filtering AF 0.0546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0487%

Overall 0.00384% 62/1,612,618 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0717%	1,394
East Asian	0.00672%	14,886
Remaining individualsnot grpmax-eligible	0.00641%	15,609
African / African-American	0.00267%	37,424
European (non-Finnish)	0.000848%	117,929

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: AKAP9
Protein: p.Arg2016Cys
Coding: c.6046C>T
MANE Select: NM_005751
dbSNP: rs376950905
Type: single nucleotide variant
Location: chr7:92065299 (GRCh38)
Gene constraint: LOEUF 0.662 · pLI <0.01 (gnomAD)

Full AKAP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

long QT syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy

Similar variants

AKAP9 p.Arg2016His Uncertain significance ★★ ⚠ same residue
AKAP9 c.10713+4A>G Uncertain significance ★★ same condition
AKAP9 c.11686+4C>T Uncertain significance ★★ same condition
AKAP9 c.11687-2A>G Uncertain significance ★★ same condition
AKAP9 c.3838-4A>G Uncertain significance ★★ same condition
AKAP9 c.3953-3T>C Uncertain significance ★★ same condition
AKAP9 c.405+3A>G Uncertain significance ★★ same condition
AKAP9 c.48+5G>A Uncertain significance ★★ same condition

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/akap9-p-arg2016cys (accessed [today's date]).

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