Is AKAP8 p.Val321Ala (c.962T>C) pathogenic?

AKAP8 p.Val321Ala (c.962T>C) is classified Likely benign in AKAP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-22). AlphaMissense: likely benign (0.0656); Ultra-rare (popmax 0.016%, afr).

How common is AKAP8 p.Val321Ala (c.962T>C) in the general population?

AKAP8 p.Val321Ala (c.962T>C) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about AKAP8 p.Val321Ala (c.962T>C)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

AKAP8 p.Val321Ala

c.962T>C · rs567716912 · VCV3106596

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.98	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 2.6	GERP -3, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 21 kb · p 0.52 · regional, not allelic
Overall
CADD	11.61	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 0.016% African / African-American · 12/74,998 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00632% 102/1,614,102 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,250
European (non-Finnish)	0.00737%	13,564
Admixed American	0.00333%	30,007
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Val321Ala
Coding: c.962T>C
MANE Select: NM_005858
dbSNP: rs567716912
Type: single nucleotide variant
Location: chr19:15372247 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 53.67
Residue 321: the 'disordered' region

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

Similar variants

AKAP8 p.Val321= Benign ★ same residue
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

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-val321ala (accessed [today's date]).

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