Is ADCK2 p.Glu366Lys (c.1096G>A) pathogenic?

ADCK2 p.Glu366Lys (c.1096G>A) is classified Uncertain significance in ADCK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-06). AlphaMissense: likely pathogenic (0.9701); Very rare (popmax 0.00667%, amr).

How common is ADCK2 p.Glu366Lys (c.1096G>A) in the general population?

ADCK2 p.Glu366Lys (c.1096G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ADCK2 p.Glu366Lys (c.1096G>A)?

AlphaMissense predicts likely pathogenic (score 0.9701) — an in-silico prediction, not a clinical call.

ADCK2 p.Glu366Lys

c.1096G>A · VCV3832913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9701	likely pathogenic · top 7% in ADCK2
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 3.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 21 kb · p 0.00024 · regional, not allelic
Overall
CADD	33.0	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 0.00667% Admixed American · 4/59,978 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00428% 69/1,613,918 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,995
South Asian	0.00659%	15,178
European (non-Finnish)	0.00475%	21,072
Remaining individualsnot grpmax-eligible	0.0032%	31,243
East Asian	0.00223%	44,878

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: ADCK2
Protein: p.Glu366Lys
Coding: c.1096G>A
MANE Select: NM_052853
Type: single nucleotide variant
Location: chr7:140679170 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.45
Residue 366: the protein kinase domain; a UniProt-annotated variant site (found in a patient with slow and progressive proximal muscle weakness with permanent myalgia both at rest and during muscular exertion which results in permanent disability; uncertain significance; decreased levels of coenzyme q10)

Full ADCK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADCK2 p.Ala217Pro Uncertain significance ★ ⚠ same type
ADCK2 p.Ala293Gly Uncertain significance ★ ⚠ same type
ADCK2 p.Ala293Val Uncertain significance ★ ⚠ same type
ADCK2 p.Ala319Thr Uncertain significance ★ ⚠ same type
ADCK2 p.Ala465Val Uncertain significance ★ ⚠ same type
ADCK2 p.Ala510Thr Uncertain significance ★ ⚠ same type
ADCK2 p.Ala78Ser Uncertain significance ★ ⚠ same type
ADCK2 p.Arg292Trp 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/adck2-p-glu366lys (accessed [today's date]).

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