Is AKAP12 p.Val415Ala (c.1244T>C) pathogenic?

AKAP12 p.Val415Ala (c.1244T>C) is classified Uncertain significance in AKAP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.2206); Very rare (popmax 0.00553%, sas).

How common is AKAP12 p.Val415Ala (c.1244T>C) in the general population?

AKAP12 p.Val415Ala (c.1244T>C) is very rare (popmax 0.00553%, sas) (gnomAD).

What do computational predictors say about AKAP12 p.Val415Ala (c.1244T>C)?

AlphaMissense predicts likely benign (score 0.2206) — an in-silico prediction, not a clinical call.

AKAP12 p.Val415Ala

c.1244T>C · VCV4262212

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2206 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00553%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2206	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.14	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 2.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 111 kb · p 0.55 · regional, not allelic
Overall
CADD	18.48	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 0.00553% South Asian · 5/90,410 alleles

Filtering AF 0.00212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000808% 13/1,608,218 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00553%	18,082
East Asian	0.00224%	44,682
Admixed American	0.00168%	59,414
African / African-American	0.00136%	73,634
European (non-Finnish)	0.000425%	235,519

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.Val415Ala
Coding: c.1244T>C
MANE Select: NM_005100
Type: single nucleotide variant
Location: chr6:151349635 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 40.98
Residue 415: the 'involved in pkc-binding' 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-val415ala (accessed [today's date]).

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