Is AK2 p.Met68Val (c.202A>G) pathogenic?

AK2 p.Met68Val (c.202A>G) is classified Conflicting classifications of pathogenicity in AK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-17). AlphaMissense: ambiguous (0.3603); Rare (popmax 0.54%, sas); Associated with reticular dysgenesis.

What condition is associated with AK2 p.Met68Val (c.202A>G)?

AK2 p.Met68Val (c.202A>G) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Met68Val (c.202A>G) in the general population?

AK2 p.Met68Val (c.202A>G) is rare (popmax 0.54%, sas) (gnomAD).

How is Reticular dysgenesis inherited?

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

What do computational predictors say about AK2 p.Met68Val (c.202A>G)?

AlphaMissense predicts ambiguous (score 0.3603) — an in-silico prediction, not a clinical call.

AK2 p.Met68Val

c.202A>G · rs548856916 · VCV724864

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3603 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.54%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

reticular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.3603	ambiguous
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -12.25	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	26.3	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

Grpmax group 0.54% South Asian · 492/91,086 alleles

Filtering AF 0.501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.485%

Overall 0.0323% 522/1,614,160 alleles · rare exomes 497/1,461,808 · genomes 25/152,352 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.54%	185
Middle Eastern	0.0665%	1,504
Remaining individualsnot grpmax-eligible	0.0352%	2,841
East Asian	0.00223%	44,882
Admixed American	0.00167%	60,026
European (non-Finnish)	0.000169%	590,012

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.Met68Val
Coding: c.202A>G
MANE Select: NM_001625
dbSNP: rs548856916
Type: single nucleotide variant
Location: chr1:33024459 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 68: the 'nmp' region; an α-helix

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

Disease context

reticular dysgenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Reticular dysgenesis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

AK2 p.Met68Thr Uncertain significance ★ ⚠ 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.Met1Val Pathogenic ★★ same condition
AK2 p.Ala212Thr 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-met68val (accessed [today's date]).

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