Is ADK p.Arg22Ter (c.64A>T) pathogenic?

ADK p.Arg22Ter (c.64A>T) is classified Likely pathogenic in ADK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). Very rare (popmax 0.00462%, nfe); Associated with adenosine kinase deficiency.

What condition is associated with ADK p.Arg22Ter (c.64A>T)?

ADK p.Arg22Ter (c.64A>T) is associated with adenosine kinase deficiency (ClinVar).

How common is ADK p.Arg22Ter (c.64A>T) in the general population?

ADK p.Arg22Ter (c.64A>T) is very rare (popmax 0.00462%, nfe) (gnomAD).

ADK p.Arg22Ter

Q: How is Hypermethioninemia encephalopathy due to adenosine kinase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.64A>T · VCV4845594

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00462%, nfe)

Conditions

adenosine kinase deficiency

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 1 of 11
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.23 · evaluated, not missing
Pangolin	Δ0.25	loss · gain 0.02 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 9.1	GERP 2.4, phastCons 1
Overall
CADD	48.0	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 0.00462% European (non-Finnish) · 53/1,146,766 alleles

Filtering AF 0.00361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00327%

Overall 0.00379% 53/1,397,234 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: ADK
Protein: p.Arg22Ter
Coding: c.64A>T
MANE Select: NM_006721
Type: single nucleotide variant
Location: chr10:74151342 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.40 · 7 PDB

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

Disease context

adenosine kinase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypermethioninemia encephalopathy due to adenosine kinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ADK p.Ala344Val Pathogenic/Likely pathogenic ★★ same condition
ADK p.Ile87Val Uncertain significance ★★ ⚠ same condition
ADK p.Lys74Glu Uncertain significance ★★ ⚠ same condition
ADK c.195-18A>G Benign/Likely benign ★★ same condition
ADK c.274-9G>T Likely benign ★★ same condition
ADK c.66-23911C>T Benign ★★ same condition
ADK c.726+11T>G Benign/Likely benign ★★ same condition
ADK c.727-11T>C Benign ★★ same condition

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/adk-p-arg22ter (accessed [today's date]).

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