Is AK2 p.Arg103Trp (c.307C>T) pathogenic?

AK2 p.Arg103Trp (c.307C>T) is classified Pathogenic/Likely pathogenic in AK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-01). AlphaMissense: likely pathogenic (0.9896); Very rare (popmax 0.00223%, eas); Associated with severe combined immunodeficiency.

What condition is associated with AK2 p.Arg103Trp (c.307C>T)?

AK2 p.Arg103Trp (c.307C>T) is associated with severe combined immunodeficiency, reticular dysgenesis (ClinVar).

How common is AK2 p.Arg103Trp (c.307C>T) in the general population?

AK2 p.Arg103Trp (c.307C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about AK2 p.Arg103Trp (c.307C>T)?

AlphaMissense predicts likely pathogenic (score 0.9896) — an in-silico prediction, not a clinical call.

AK2 p.Arg103Trp

c.307C>T · rs267606648 · VCV18260

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe combined immunodeficiency

Computational evidence

Protein change
AlphaMissense	0.9896	likely pathogenic ✓ concordant with ClinVar
REVEL	0.766	pathogenic-leaning
SaProt	LLR -17.83	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 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	33.0	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 · 1/44,900 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,613,962 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,900
African / African-American	0.00133%	74,914
European (non-Finnish)	0.000254%	393,318

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.Arg103Trp
Coding: c.307C>T
MANE Select: NM_001625
dbSNP: rs267606648
Type: single nucleotide variant
Location: chr1:33021616 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 3 PDB
Residue 103: a binding site; a UniProt-annotated variant site (in rdys)

Full AK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe combined immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: reticular dysgenesis

Similar variants

AK2 p.Arg103= Likely benign ★★ same residue
AK2 p.Arg103Pro 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.Arg175Pro Likely pathogenic ★★ same condition
AK2 p.Met1Val Pathogenic ★★ same condition
AK2 p.Ala212Thr 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-arg103trp (accessed [today's date]).

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