Is AK2 p.Ile83Val (c.247A>G) pathogenic?

AK2 p.Ile83Val (c.247A>G) is classified Uncertain significance in AK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-25). AlphaMissense: likely benign (0.2204); Rare (popmax 0.115%, mid); Associated with reticular dysgenesis.

What condition is associated with AK2 p.Ile83Val (c.247A>G)?

AK2 p.Ile83Val (c.247A>G) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Ile83Val (c.247A>G) in the general population?

AK2 p.Ile83Val (c.247A>G) is rare (popmax 0.115%, mid) (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.Ile83Val (c.247A>G)?

AlphaMissense predicts likely benign (score 0.2204) — an in-silico prediction, not a clinical call.

AK2 p.Ile83Val

c.247A>G · rs184683619 · VCV577089

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2204 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

reticular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.2204	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.115% Middle Eastern · 7/6,062 alleles

Filtering AF 0.0708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0639%

Overall 0.0566% 914/1,613,880 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	866
Admixed American	0.09%	1,111
European (non-Finnish)	0.066%	1,514
Remaining individualsnot grpmax-eligible	0.0608%	1,645
African / African-American	0.0333%	3,001
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,230
Finnishnot grpmax-eligible	0.00312%	32,017
South Asian	0.0022%	45,540

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.Ile83Val
Coding: c.247A>G
MANE Select: NM_001625
dbSNP: rs184683619
Type: single nucleotide variant
Location: chr1:33021676 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 83: a disulfide bond; 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-ile83val (accessed [today's date]).

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