Is ADK p.Asp235Ala (c.704A>C) pathogenic?

ADK p.Asp235Ala (c.704A>C) is classified Pathogenic in ADK (ClinVar, No assertion criteria, 1 submitter; last evaluated 2011-10-07). AlphaMissense: likely pathogenic (0.979); Absent from gnomAD v4.1; Associated with adenosine kinase deficiency.

What condition is associated with ADK p.Asp235Ala (c.704A>C)?

ADK p.Asp235Ala (c.704A>C) is associated with adenosine kinase deficiency (ClinVar).

How common is ADK p.Asp235Ala (c.704A>C) in the general population?

ADK p.Asp235Ala (c.704A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADK p.Asp235Ala (c.704A>C)?

AlphaMissense predicts likely pathogenic (score 0.979) — an in-silico prediction, not a clinical call.

ADK p.Asp235Ala

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.704A>C · rs397514453 · VCV29604

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adenosine kinase deficiency

Computational evidence

Protein change
AlphaMissense	0.979	likely pathogenic ✓ concordant with ClinVar · top 8% in ADK
REVEL	0.969	strongly pathogenic-leaning
SaProt	LLR -16.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 557 kb · p 4.5e-07 · regional, not allelic
Overall
CADD	27.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADK
Protein: p.Asp235Ala
Coding: c.704A>C
MANE Select: NM_006721
dbSNP: rs397514453
Type: single nucleotide variant
Location: chr10:74525404 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.40 · 7 PDB
Residue 235: a UniProt-annotated variant site (in hmakd); a UniProt-annotated variant site (in hmakd; abolished ability to mediate phosphorylation of unmodified and modified adenosines); a β-strand

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.Asp235= Benign ★★ same residue
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

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-asp235ala (accessed [today's date]).

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