Is AK2 p.Val219Met (c.655G>A) pathogenic?

AK2 p.Val219Met (c.655G>A) is classified Uncertain significance in AK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-04). AlphaMissense: likely pathogenic (0.9577); Very rare (popmax 0.00667%, amr); Associated with reticular dysgenesis.

What condition is associated with AK2 p.Val219Met (c.655G>A)?

AK2 p.Val219Met (c.655G>A) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Val219Met (c.655G>A) in the general population?

AK2 p.Val219Met (c.655G>A) is very rare (popmax 0.00667%, amr) (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.Val219Met (c.655G>A)?

AlphaMissense predicts likely pathogenic (score 0.9577) — an in-silico prediction, not a clinical call.

AK2 p.Val219Met

c.655G>A · rs755736918 · VCV664531

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9577 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

reticular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.9577	likely pathogenic
REVEL	0.74	pathogenic-leaning
SaProt	LLR -12.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,994 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00545% 88/1,614,028 alleles · very rare exomes 83/1,461,888 · genomes 5/152,140 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Admixed Americangrpmax	0.00667%	14,999
European (non-Finnish)	0.00627%	15,946
African / African-American	0.00267%	37,453
Finnishnot grpmax-eligible	0.00156%	64,020
South Asian	0.0011%	91,088

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.Val219Met
Coding: c.655G>A
MANE Select: NM_001625
dbSNP: rs755736918
Type: single nucleotide variant
Location: chr1:33013246 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 219: 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-val219met (accessed [today's date]).

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