Is AK2 p.Ile167fs (c.498_499dup) pathogenic?

AK2 p.Ile167fs (c.498499dup) is classified Likely pathogenic in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-11). Very rare (popmax 0.00502%, amr); Associated with severe combined immunodeficiency.

What condition is associated with AK2 p.Ile167fs (c.498_499dup)?

AK2 p.Ile167fs (c.498_499dup) is associated with severe combined immunodeficiency (ClinVar).

How common is AK2 p.Ile167fs (c.498_499dup) in the general population?

AK2 p.Ile167fs (c.498_499dup) is very rare (popmax 0.00502%, amr) (gnomAD).

AK2 p.Ile167fs

c.498_499dup · rs1638975235 · VCV1339680

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 0.00502%, amr)

Conditions

severe combined immunodeficiency

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 11	GERP 2.8, phastCons 1
Overall
CADD	33.0	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 0.00502% Admixed American · 3/59,740 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.00123% 18/1,459,998 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00502%	19,913
East Asian	0.00223%	44,844
African / African-American	0.00134%	74,894
European (non-Finnish)	0.0011%	90,690

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.Ile167fs
Coding: c.498_499dup
MANE Select: NM_001625
dbSNP: rs1638975235
Type: Insertion
Location: chr1:33013401 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 167: the 'lid' region; the 'disordered' region; a β-strand

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

Disease context

severe combined immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AK2 c.498+1G>A Pathogenic/Likely pathogenic ★★ same condition
AK2 p.Arg103Trp Pathogenic/Likely pathogenic ★★ same condition
AK2 p.Met1Val Pathogenic ★★ same condition
AK2 c.330+1G>C Likely pathogenic ★ same condition
AK2 p.Arg175Gly Likely pathogenic ★ same condition
AK2 p.Arg186Cys Likely pathogenic ★ same condition
AK2 p.Tyr200Ter Likely pathogenic ★ same condition
AK2 p.Leu235delinsSerTer 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/ak2-p-ile167fs (accessed [today's date]).

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