Is AKAP12 p.Pro459Ser (c.1375C>T) pathogenic?

AKAP12 p.Pro459Ser (c.1375C>T) is classified Uncertain significance in AKAP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-08). AlphaMissense: likely benign (0.1145); Very rare (popmax 8.47e-05%, nfe).

How common is AKAP12 p.Pro459Ser (c.1375C>T) in the general population?

AKAP12 p.Pro459Ser (c.1375C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AKAP12 p.Pro459Ser (c.1375C>T)?

AlphaMissense predicts likely benign (score 0.1145) — an in-silico prediction, not a clinical call.

AKAP12 p.Pro459Ser

c.1375C>T · rs771228267 · VCV2300195

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1145 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1145	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.61	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 -0.88	GERP -0.76
Regional constraint	o/e 0.98	unconstrained · MANE · 111 kb · p 0.55 · regional, not allelic
Overall
CADD	3.988	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 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.84e-05% 1/1,461,852 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: AKAP12
Protein: p.Pro459Ser
Coding: c.1375C>T
MANE Select: NM_005100
dbSNP: rs771228267
Type: single nucleotide variant
Location: chr6:151349766 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 40.98
Residue 459: the 'involved in pkc-binding' region; the 'disordered' region

Full AKAP12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AKAP12 p.Pro15Arg Uncertain significance ★★ ⚠ same type
AKAP12 p.Ala1074Val Uncertain significance ★ ⚠ same type
AKAP12 p.Ala1081Asp Uncertain significance ★ ⚠ same type
AKAP12 p.Ala1141Thr Uncertain significance ★ ⚠ same type
AKAP12 p.Ala1145Asp Uncertain significance ★ ⚠ same type
AKAP12 p.Ala1145Thr Uncertain significance ★ ⚠ same type
AKAP12 p.Ala1201Thr Uncertain significance ★ ⚠ same type
AKAP12 p.Ala129Val Uncertain significance ★ ⚠ 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/akap12-p-pro459ser (accessed [today's date]).

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