Is ATIC p.Thr498= (c.1494C>G) pathogenic?

ATIC p.Thr498= (c.1494C>G) is classified Benign/Likely benign in ATIC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-01). Low-frequency (popmax 2.18%, mid); Associated with AICA-ribosiduria.

What condition is associated with ATIC p.Thr498= (c.1494C>G)?

ATIC p.Thr498= (c.1494C>G) is associated with AICA-ribosiduria (ClinVar).

How common is ATIC p.Thr498= (c.1494C>G) in the general population?

ATIC p.Thr498= (c.1494C>G) is low-frequency (popmax 2.18%, mid) (gnomAD).

How is AICA-ribosiduria inherited?

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

ATIC p.Thr498=

c.1494C>G · rs116255553 · VCV784586

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.18%, mid)

Conditions

AICA-ribosiduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.077	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.004	GERP -0.78, phastCons 0.79
Overall
CADD	5.74	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.18% Middle Eastern · 132/6,062 alleles

Filtering AF 1.88% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.76%

Overall 0.812% 13,105/1,614,114 alleles · low-frequency exomes 12,119/1,461,840 · genomes 986/152,274 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.18%	46
European (non-Finnish)	0.97%	103
Admixed American	0.771%	130
Remaining individualsnot grpmax-eligible	0.77%	130
Amishnot grpmax-eligible	0.768%	130
Ashkenazi Jewishnot grpmax-eligible	0.324%	308
South Asian	0.307%	325
African / African-American	0.191%	525
Finnishnot grpmax-eligible	0.0906%	1,104

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.Thr498=
Coding: c.1494C>G
MANE Select: NM_004044
dbSNP: rs116255553
Type: single nucleotide variant
Location: chr2:215346932 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 498: the 'aicar formyltransferase' region

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-thr498 (accessed [today's date]).

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