Is ATIC p.Asn489Ser (c.1466A>G) pathogenic?

ATIC p.Asn489Ser (c.1466A>G) is classified Uncertain significance in ATIC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: ambiguous (0.3728); Rare (popmax 0.16%, eas); Associated with AICA-ribosiduria.

What condition is associated with ATIC p.Asn489Ser (c.1466A>G)?

ATIC p.Asn489Ser (c.1466A>G) is associated with AICA-ribosiduria (ClinVar).

How common is ATIC p.Asn489Ser (c.1466A>G) in the general population?

ATIC p.Asn489Ser (c.1466A>G) is rare (popmax 0.16%, eas) (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.Asn489Ser (c.1466A>G)?

AlphaMissense predicts ambiguous (score 0.3728) — an in-silico prediction, not a clinical call.

ATIC p.Asn489Ser

c.1466A>G · VCV3585398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3728 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.16%, eas)

Conditions

AICA-ribosiduria

Computational evidence

Protein change
AlphaMissense	0.3728	ambiguous
REVEL	0.629	indeterminate
SaProt	LLR -7.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	26.5	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 0.16% East Asian · 72/44,886 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.12%

Overall 0.0138% 222/1,614,238 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.16%	623
European (non-Finnish)	0.0112%	8,940
Remaining individualsnot grpmax-eligible	0.0096%	10,419
African / African-American	0.00666%	15,014
Finnishnot grpmax-eligible	0.00468%	21,349
South Asian	0.00329%	30,361
Admixed American	0.00167%	60,034

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.Asn489Ser
Coding: c.1466A>G
MANE Select: NM_004044
Type: single nucleotide variant
Location: chr2:215346904 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 489: 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-asn489ser (accessed [today's date]).

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