Is ADCK2 p.Arg333Ter (c.997C>T) pathogenic?

ADCK2 p.Arg333Ter (c.997C>T) is classified Uncertain significance in ADCK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-10-02). Ultra-rare (popmax 0.0165%, mid).

How common is ADCK2 p.Arg333Ter (c.997C>T) in the general population?

ADCK2 p.Arg333Ter (c.997C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

ADCK2 p.Arg333Ter

c.997C>T · VCV3893213

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 8
REVEL	0.341	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 3.8, phastCons 0.98
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00118% 19/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
African / African-American	0.00534%	18,718
European (non-Finnish)	0.0011%	90,771
South Asian	0.0011%	91,062

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.Arg333Ter
Coding: c.997C>T
MANE Select: NM_052853
Type: single nucleotide variant
Location: chr7:140674674 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.45
Residue 333: 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-arg333ter (accessed [today's date]).

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