Is AK2 p.Pro216= (c.648C>T) pathogenic?

AK2 p.Pro216= (c.648C>T) is classified Likely benign in AK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-21). Ultra-rare (popmax 0.0159%, nfe); Associated with reticular dysgenesis.

What condition is associated with AK2 p.Pro216= (c.648C>T)?

AK2 p.Pro216= (c.648C>T) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Pro216= (c.648C>T) in the general population?

AK2 p.Pro216= (c.648C>T) is ultra-rare (popmax 0.0159%, nfe) (gnomAD).

How is Reticular dysgenesis inherited?

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

AK2 p.Pro216=

c.648C>T · rs201622956 · VCV1086743

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0159%, 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 0.11	GERP -5.5, phastCons 0.17
Overall
CADD	7.822	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0159% European (non-Finnish) · 187/1,176,802 alleles

Filtering AF 0.014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.0128% 206/1,605,934 alleles · ultra-rare exomes 190/1,456,630 · genomes 16/149,304 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.111%	900
European (non-Finnish)grpmax	0.0159%	6,293
African / African-American	0.00946%	10,566
Finnishnot grpmax-eligible	0.0065%	15,388
Admixed American	0.00504%	19,841
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,536
East Asian	0.00224%	44,742
South Asian	0.00221%	45,267

Amish 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.Pro216=
Coding: c.648C>T
MANE Select: NM_001625
dbSNP: rs201622956
Type: single nucleotide variant
Location: chr1:33013253 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 216: 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.Pro216Ser 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-pro216 (accessed [today's date]).

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