Is ATIC p.Lys426Arg (c.1277A>G) pathogenic?

ATIC p.Lys426Arg (c.1277A>G) is classified Conflicting classifications of pathogenicity in ATIC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-05-12). AlphaMissense: likely benign (0.3217); Very rare (popmax 0.00254%, nfe); Associated with AICA-ribosiduria.

What condition is associated with ATIC p.Lys426Arg (c.1277A>G)?

ATIC p.Lys426Arg (c.1277A>G) is associated with AICA-ribosiduria (ClinVar).

How common is ATIC p.Lys426Arg (c.1277A>G) in the general population?

ATIC p.Lys426Arg (c.1277A>G) is very rare (popmax 0.00254%, nfe) (gnomAD).

How is AICA-ribosiduria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ATIC p.Lys426Arg (c.1277A>G)?

AlphaMissense predicts likely benign (score 0.3217) — an in-silico prediction, not a clinical call.

ATIC p.Lys426Arg

c.1277A>G · rs121434478 · VCV7810

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3217 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AICA-ribosiduria

Computational evidence

Protein change
AlphaMissense	0.3217	likely benign
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -10.25	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	29.4	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 0.00254% European (non-Finnish) · 30/1,180,020 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00204% 33/1,613,922 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,334
Admixed American	0.00167%	59,978
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,884

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: ATIC
Protein: p.Lys426Arg
Coding: c.1277A>G
MANE Select: NM_004044
dbSNP: rs121434478
Type: single nucleotide variant
Location: chr2:215344828 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 426: a UniProt-annotated variant site (in aicar; loss of transformylase activity); the 'aicar formyltransferase' region; an α-helix

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

Disease context

AICA-ribosiduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For AICA-ribosiduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ATIC p.Ala183Glu Uncertain significance ★★ ⚠ same condition
ATIC p.His584Arg Uncertain significance ★★ ⚠ same condition
ATIC c.1098+60C>G Benign ★★ same condition
ATIC c.1228-30A>G Benign ★★ same condition
ATIC c.147-111A>T Benign ★★ same condition
ATIC c.1503+48A>T Benign ★★ same condition
ATIC c.380-18G>A Likely benign ★★ same condition
ATIC c.380-19A>C Benign ★★ 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/atic-p-lys426arg (accessed [today's date]).

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