Is AKAP9 p.Ala458Pro (c.1372G>C) pathogenic?

AKAP9 p.Ala458Pro (c.1372G>C) is classified Benign/Likely benign in AKAP9 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.457); Rare (popmax 0.833%, afr); Associated with Cardiovascular phenotype.

What condition is associated with AKAP9 p.Ala458Pro (c.1372G>C)?

AKAP9 p.Ala458Pro (c.1372G>C) is associated with Cardiovascular phenotype, long QT syndrome, dilated cardiomyopathy (ClinVar).

How common is AKAP9 p.Ala458Pro (c.1372G>C) in the general population?

AKAP9 p.Ala458Pro (c.1372G>C) is rare (popmax 0.833%, afr) (gnomAD).

What do computational predictors say about AKAP9 p.Ala458Pro (c.1372G>C)?

AlphaMissense predicts ambiguous (score 0.457) — an in-silico prediction, not a clinical call.

AKAP9 p.Ala458Pro

c.1372G>C · rs143894795 · VCV191551

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.457 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.833%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.457	ambiguous
REVEL	0.052	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP 2.8, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 130 kb · p 0.16 · regional, not allelic
Overall
CADD	16.24	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 0.833% African / African-American · 625/75,008 alleles

Filtering AF 0.779% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.758%

Overall 0.0437% 705/1,613,920 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.833%	120
Remaining individualsnot grpmax-eligible	0.0624%	1,603
Admixed American	0.0483%	2,069
Middle Eastern	0.033%	3,030
South Asian	0.00439%	22,771
European (non-Finnish)	0.000509%	196,651

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.Ala458Pro
Coding: c.1372G>C
MANE Select: NM_005751
dbSNP: rs143894795
Type: single nucleotide variant
Location: chr7:92001289 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome dilated cardiomyopathy long QT syndrome 11

Similar variants

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.3952+2T>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-ala458pro (accessed [today's date]).

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