Is AK2 p.Ser129Asn (c.386G>A) pathogenic?

AK2 p.Ser129Asn (c.386G>A) is classified Conflicting classifications of pathogenicity in AK2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1302); Rare (popmax 0.663%, nfe); Associated with reticular dysgenesis.

What condition is associated with AK2 p.Ser129Asn (c.386G>A)?

AK2 p.Ser129Asn (c.386G>A) is associated with reticular dysgenesis (ClinVar).

How common is AK2 p.Ser129Asn (c.386G>A) in the general population?

AK2 p.Ser129Asn (c.386G>A) is rare (popmax 0.663%, nfe) (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.Ser129Asn (c.386G>A)?

AlphaMissense predicts likely benign (score 0.1302) — an in-silico prediction, not a clinical call.

AK2 p.Ser129Asn

c.386G>A · rs61750965 · VCV517906

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1302 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.663%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

reticular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.1302	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.8, phastCons 0.99
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	18.33	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 0.663% European (non-Finnish) · 7,826/1,179,942 alleles

Filtering AF 0.651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.646%

Overall 0.56% 9,036/1,614,038 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.663%	151
Ashkenazi Jewishnot grpmax-eligible	0.645%	155
South Asian	0.549%	182
Middle Eastern	0.511%	196
Remaining individualsnot grpmax-eligible	0.503%	199
African / African-American	0.125%	798
Admixed American	0.085%	1,177
Finnishnot grpmax-eligible	0.0437%	2,287
East Asian	0.00223%	44,886

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.Ser129Asn
Coding: c.386G>A
MANE Select: NM_001625
dbSNP: rs61750965
Type: single nucleotide variant
Location: chr1:33021406 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 129: 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.Ser129= Likely benign ★ same residue
AK2 p.Ser129Arg 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-ser129asn (accessed [today's date]).

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