Is AKAP6 p.Arg1069Cys (c.3205C>T) pathogenic?

AKAP6 p.Arg1069Cys (c.3205C>T) is classified Uncertain significance in AKAP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely benign (0.1278); Ultra-rare (popmax 0.0165%, mid).

How common is AKAP6 p.Arg1069Cys (c.3205C>T) in the general population?

AKAP6 p.Arg1069Cys (c.3205C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about AKAP6 p.Arg1069Cys (c.3205C>T)?

AlphaMissense predicts likely benign (score 0.1278) — an in-silico prediction, not a clinical call.

AKAP6 p.Arg1069Cys

c.3205C>T · VCV3515197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1278 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1278	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 3.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 279 kb · p 0.34 · regional, not allelic
Overall
CADD	27.0	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 0.0165% Middle Eastern · 1/6,046 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00329% 53/1,613,364 alleles · ultra-rare exomes 43/1,461,302 · genomes 10/152,062 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,046
South Asian	0.00988%	10,118
African / African-American	0.00801%	12,486
East Asian	0.00669%	14,949
Admixed American	0.00668%	14,966
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)	0.00237%	42,133

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: AKAP6
Protein: p.Arg1069Cys
Coding: c.3205C>T
MANE Select: NM_004274
Type: single nucleotide variant
Location: chr14:32735715 (GRCh38)
Gene constraint: LOEUF 0.367 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 43.07

Full AKAP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AKAP6 p.Arg1069His Uncertain significance ★ ⚠ same residue
AKAP6 p.Arg1069Ser Uncertain significance ★ ⚠ same residue
AKAP6 p.Asn558Asp Benign ★★ same type
AKAP6 p.Glu2168= Benign ★★ same type
AKAP6 p.Glu892Lys Benign ★★ same type
AKAP6 p.Thr1516Ala Benign ★★ same type
AKAP6 p.Ala1022Val Uncertain significance ★ ⚠ same type
AKAP6 p.Ala123Asp 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/akap6-p-arg1069cys (accessed [today's date]).

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