Is AKAP1 p.Ala406Asp (c.1217C>A) pathogenic?

AKAP1 p.Ala406Asp (c.1217C>A) is classified Uncertain significance in AKAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.1237); Very rare (popmax 0.000678%, nfe).

How common is AKAP1 p.Ala406Asp (c.1217C>A) in the general population?

AKAP1 p.Ala406Asp (c.1217C>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about AKAP1 p.Ala406Asp (c.1217C>A)?

AlphaMissense predicts likely benign (score 0.1237) — an in-silico prediction, not a clinical call.

AKAP1 p.Ala406Asp

c.1217C>A · rs763062892 · VCV2237188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1237	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -6.58	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 0.34	GERP 1.7
Regional constraint	o/e 0.81	unconstrained · MANE · 14 kb · p 5.3e-08 · regional, not allelic
Overall
CADD	18.05	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 0.000678% European (non-Finnish) · 8/1,180,046 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,118 alleles · very rare exomes 8/1,461,796 · genomes 0/152,322 · joint denominator

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: AKAP1
Protein: p.Ala406Asp
Coding: c.1217C>A
MANE Select: NM_003488
dbSNP: rs763062892
Type: single nucleotide variant
Location: chr17:57106681 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.67 (gnomAD)
Structure: AlphaFold pLDDT 57.02

Full AKAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AKAP1 c.1976-6A>G Benign ★★ same type
AKAP1 p.Ala218Thr Benign ★★ same type
AKAP1 p.Gly323Ser Benign ★★ same type
AKAP1 p.Pro475= Benign ★★ same type
AKAP1 p.Pro818= Benign ★★ same type
AKAP1 p.Ser330Gly Benign ★★ same type
AKAP1 p.Ser388= Benign ★★ same type
AKAP1 p.Thr521Ile Likely benign ★★ 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/akap1-p-ala406asp (accessed [today's date]).

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