Is AKAP9 p.Arg3476Ser (c.10428A>T) pathogenic?

AKAP9 p.Arg3476Ser (c.10428A>T) is classified Uncertain significance in AKAP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-04). AlphaMissense: likely pathogenic (0.9588); Very rare (popmax 0.000424%, nfe); Associated with long QT syndrome.

What condition is associated with AKAP9 p.Arg3476Ser (c.10428A>T)?

AKAP9 p.Arg3476Ser (c.10428A>T) is associated with long QT syndrome (ClinVar).

How common is AKAP9 p.Arg3476Ser (c.10428A>T) in the general population?

AKAP9 p.Arg3476Ser (c.10428A>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about AKAP9 p.Arg3476Ser (c.10428A>T)?

AlphaMissense predicts likely pathogenic (score 0.9588) — an in-silico prediction, not a clinical call.

AKAP9 p.Arg3476Ser

c.10428A>T · VCV4752198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9588 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.9588	likely pathogenic · top 2% in AKAP9
REVEL	0.081	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.97 · regional, not allelic
Overall
CADD	21.3	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 0.000424% European (non-Finnish) · 5/1,180,022 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,656 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: AKAP9
Protein: p.Arg3476Ser
Coding: c.10428A>T
MANE Select: NM_005751
Type: single nucleotide variant
Location: chr7:92097615 (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

Similar variants

AKAP9 p.Arg3476= Benign/Likely benign ★★ same residue
AKAP9 p.Arg3476Ter 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

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-arg3476ser (accessed [today's date]).

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