Is AK2 p.Leu111= (c.333C>T) pathogenic?

AK2 p.Leu111= (c.333C>T) is classified Likely benign in AK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0324%, nfe); Associated with reticular dysgenesis.

What condition is associated with AK2 p.Leu111= (c.333C>T)?

AK2 p.Leu111= (c.333C>T) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Leu111= (c.333C>T) in the general population?

AK2 p.Leu111= (c.333C>T) is ultra-rare (popmax 0.0324%, nfe) (gnomAD).

How is Reticular dysgenesis inherited?

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

AK2 p.Leu111=

c.333C>T · rs200433299 · VCV1116104

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0324%, nfe)

Conditions

reticular dysgenesis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.1	GERP -5.5
Overall
CADD	2.111	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0324% European (non-Finnish) · 382/1,179,918 alleles

Filtering AF 0.0297% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.0261% 421/1,613,822 alleles · ultra-rare exomes 400/1,461,772 · genomes 21/152,050 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.056%	1,785
European (non-Finnish)grpmax	0.0324%	3,089
Admixed American	0.00333%	29,995
East Asian	0.00223%	44,888
African / African-American	0.00134%	74,876

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu111=
Coding: c.333C>T
MANE Select: NM_001625
dbSNP: rs200433299
Type: single nucleotide variant
Location: chr1:33021459 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 111: 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 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-leu111 (accessed [today's date]).

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