Is AK2 p.Met1Val (c.1A>G) pathogenic?

AK2 p.Met1Val (c.1A>G) is classified Pathogenic in AK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-10). Very rare (popmax 0.00228%, sas); Associated with severe combined immunodeficiency.

What condition is associated with AK2 p.Met1Val (c.1A>G)?

AK2 p.Met1Val (c.1A>G) is associated with severe combined immunodeficiency, reticular dysgenesis (ClinVar).

How common is AK2 p.Met1Val (c.1A>G) in the general population?

AK2 p.Met1Val (c.1A>G) is very rare (popmax 0.00228%, sas) (gnomAD).

AK2 p.Met1Val

c.1A>G · rs137853206 · VCV18252

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00228%, sas)

Conditions

severe combined immunodeficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.556	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Overall
CADD	21.0	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 0.00228% South Asian · 2/87,834 alleles

Filtering AF 0.000378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.000765% 11/1,437,220 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00228%	43,917
Admixed American	0.00176%	56,916
European (non-Finnish)	0.000685%	146,081

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.Met1Val
Coding: c.1A>G
MANE Select: NM_001625
dbSNP: rs137853206
Type: single nucleotide variant
Location: chr1:33036828 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 1: a modified residue (n-acetylmethionine)

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

Also linked: reticular dysgenesis

Similar variants

AK2 p.Met1Ile Pathogenic ★ same residue
AK2 c.330+5G>A Pathogenic ★★ same condition
AK2 c.498+1G>A Pathogenic/Likely pathogenic ★★ same condition
AK2 p.Ala182Asp Pathogenic/Likely pathogenic ★★ same condition
AK2 p.Arg103Trp Pathogenic/Likely pathogenic ★★ same condition
AK2 p.Arg175Pro Likely pathogenic ★★ same condition
AK2 p.Ala212Thr Uncertain significance ★★ ⚠ same condition
AK2 p.Ala2Val Uncertain significance ★★ ⚠ 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/ak2-p-met1val (accessed [today's date]).

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