Is AKAP8 p.Ala575Val (c.1724C>T) pathogenic?

AKAP8 p.Ala575Val (c.1724C>T) is classified Uncertain significance in AKAP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-23). AlphaMissense: likely benign (0.1376); Very rare (popmax 0.005%, amr).

How common is AKAP8 p.Ala575Val (c.1724C>T) in the general population?

AKAP8 p.Ala575Val (c.1724C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about AKAP8 p.Ala575Val (c.1724C>T)?

AlphaMissense predicts likely benign (score 0.1376) — an in-silico prediction, not a clinical call.

AKAP8 p.Ala575Val

c.1724C>T · VCV3515610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1376 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1376	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -7.16	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 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 432 bp · p 0.43 · regional, not allelic
Overall
CADD	19.53	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 0.005% Admixed American · 3/59,986 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000744% 12/1,612,872 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,995
South Asian	0.00439%	22,772
African / African-American	0.00134%	74,906
European (non-Finnish)	0.000339%	295,006

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: AKAP8
Protein: p.Ala575Val
Coding: c.1724C>T
MANE Select: NM_005858
Type: single nucleotide variant
Location: chr19:15355270 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 53.67
Residue 575: the 'rii-binding' region

Full AKAP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AKAP8 p.Ala40Thr Uncertain significance ★★ ⚠ same type
AKAP8 c.1072+7A>C Benign ★★ same type
AKAP8 p.Ala615= Benign ★★ same type
AKAP8 p.Arg206His Benign ★★ ⚠ same type
AKAP8 p.Arg320Gln Likely benign ★★ ⚠ same type
AKAP8 p.Asp687= Likely benign ★★ same type
AKAP8 p.Glu226Lys Likely benign ★★ same type
AKAP8 p.Gly167Glu 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/akap8-p-ala575val (accessed [today's date]).

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