Is AK2 p.Ser208Pro (c.622T>C) pathogenic?

AK2 p.Ser208Pro (c.622T>C) is classified Uncertain significance in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-10). AlphaMissense: likely pathogenic (0.9123); Absent from gnomAD v4.1; Associated with reticular dysgenesis.

What condition is associated with AK2 p.Ser208Pro (c.622T>C)?

AK2 p.Ser208Pro (c.622T>C) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Ser208Pro (c.622T>C) in the general population?

AK2 p.Ser208Pro (c.622T>C) is absent from gnomAD v4.1 (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.Ser208Pro (c.622T>C)?

AlphaMissense predicts likely pathogenic (score 0.9123) — an in-silico prediction, not a clinical call.

AK2 p.Ser208Pro

c.622T>C · rs776378314 · VCV1001459

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9123 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

reticular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.9123	likely pathogenic
REVEL	0.18	moderately benign-leaning
SaProt	LLR -12.86	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.69, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	19.75	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AK2
Protein: p.Ser208Pro
Coding: c.622T>C
MANE Select: NM_001625
dbSNP: rs776378314
Type: single nucleotide variant
Location: chr1:33013279 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 208: 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 p.Ser208= Likely benign ★★ same residue
AK2 p.Ser208Ala 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

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-ser208pro (accessed [today's date]).

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