Is AK2 p.Ala182Val (c.545C>T) pathogenic?

AK2 p.Ala182Val (c.545C>T) is classified Uncertain significance in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-13). AlphaMissense: ambiguous (0.4563); Very rare (popmax 0.00223%, eas); Associated with reticular dysgenesis.

What condition is associated with AK2 p.Ala182Val (c.545C>T)?

AK2 p.Ala182Val (c.545C>T) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Ala182Val (c.545C>T) in the general population?

AK2 p.Ala182Val (c.545C>T) is very rare (popmax 0.00223%, eas) (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.Ala182Val (c.545C>T)?

AlphaMissense predicts ambiguous (score 0.4563) — an in-silico prediction, not a clinical call.

AK2 p.Ala182Val

c.545C>T · rs559947967 · VCV1351210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4563 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

reticular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.4563	ambiguous
REVEL	0.551	indeterminate
SaProt	LLR -8.26	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	27.5	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 0.00223% East Asian · 1/44,886 alleles

Overall 0.000657% 1/152,310 alleles · very rare

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.Ala182Val
Coding: c.545C>T
MANE Select: NM_001625
dbSNP: rs559947967
Type: single nucleotide variant
Location: chr1:33013356 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 182: 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.Ala182Asp Pathogenic/Likely pathogenic ★★ same residue
AK2 c.330+5G>A Pathogenic ★★ same condition
AK2 c.498+1G>A 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-ala182val (accessed [today's date]).

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