Is AK2 p.Thr192fs (c.575del) pathogenic?

AK2 p.Thr192fs (c.575del) is classified Likely pathogenic in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-08). Very rare (popmax 8.48e-05%, nfe); Associated with AK2-related disorder.

What condition is associated with AK2 p.Thr192fs (c.575del)?

AK2 p.Thr192fs (c.575del) is associated with AK2-related disorder (ClinVar).

How common is AK2 p.Thr192fs (c.575del) in the general population?

AK2 p.Thr192fs (c.575del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

AK2 p.Thr192fs

c.575del · VCV4965666

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

AK2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.015	GERP -5.5, phastCons 0.031

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,936 alleles

Overall 6.84e-05% 1/1,461,796 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: AK2
Protein: p.Thr192fs
Coding: c.575del
MANE Select: NM_001625
Type: Deletion
Location: chr1:33013326 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 192: an α-helix

Full AK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AK2-related disorder

Similar variants

AK2 p.Thr192Asn Uncertain significance ★ ⚠ same residue
AK2 p.Ala182Asp Pathogenic/Likely pathogenic ★★ same condition
AK2 c.-6G>A Likely benign same condition
AK2 c.*2G>A Likely benign same condition
AK2 p.Ala212_Ter240delinsXaa Likely pathogenic ★ same type
AK2 p.Gly205fs Likely pathogenic ★ same type
AK2 p.Tyr152fs Pathogenic ★ same type
AK2 p.Val219fs Likely pathogenic ★ 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/ak2-p-thr192fs (accessed [today's date]).

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