Is AK2 p.Ala18= (c.54C>T) pathogenic?

AK2 p.Ala18= (c.54C>T) is classified Benign/Likely benign in AK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-18). Low-frequency (popmax 1.37%, nfe); Associated with reticular dysgenesis.

What condition is associated with AK2 p.Ala18= (c.54C>T)?

AK2 p.Ala18= (c.54C>T) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Ala18= (c.54C>T) in the general population?

AK2 p.Ala18= (c.54C>T) is low-frequency (popmax 1.37%, nfe) (gnomAD).

How is Reticular dysgenesis inherited?

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

AK2 p.Ala18=

c.54C>T · rs76061645 · VCV1165996

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.37%, nfe)

Conditions

reticular dysgenesis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	GERP -5.5, phastCons 0.013
Overall
CADD	11.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.37% European (non-Finnish) · 14,677/1,067,606 alleles

Filtering AF 1.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.35%

Overall 1.12% 16,488/1,478,344 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.37%	73
Remaining individualsnot grpmax-eligible	0.899%	111
Middle Eastern	0.868%	115
African / African-American	0.661%	151
Ashkenazi Jewishnot grpmax-eligible	0.491%	204
South Asian	0.411%	244
East Asian	0.241%	416
Admixed American	0.201%	496
Finnishnot grpmax-eligible	0.115%	871

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.Ala18=
Coding: c.54C>T
MANE Select: NM_001625
dbSNP: rs76061645
Type: single nucleotide variant
Location: chr1:33036775 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 18: a β-strand

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 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
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-ala18 (accessed [today's date]).

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