Is ATIC p.Ala183Glu (c.548C>A) pathogenic?

ATIC p.Ala183Glu (c.548C>A) is classified Uncertain significance in ATIC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.6093); Ultra-rare (popmax 0.0495%, mid); Associated with AICA-ribosiduria.

What condition is associated with ATIC p.Ala183Glu (c.548C>A)?

ATIC p.Ala183Glu (c.548C>A) is associated with AICA-ribosiduria (ClinVar).

How common is ATIC p.Ala183Glu (c.548C>A) in the general population?

ATIC p.Ala183Glu (c.548C>A) is ultra-rare (popmax 0.0495%, mid) (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.Ala183Glu (c.548C>A)?

AlphaMissense predicts likely pathogenic (score 0.6093) — an in-silico prediction, not a clinical call.

ATIC p.Ala183Glu

c.548C>A · rs761526509 · VCV638424

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AICA-ribosiduria

Computational evidence

Protein change
AlphaMissense	0.6093	likely pathogenic
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -12.25	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 5.8	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,058 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00217% 35/1,613,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
South Asian	0.0264%	3,795
Admixed American	0.005%	19,993
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.000254%	393,345

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.Ala183Glu
Coding: c.548C>A
MANE Select: NM_004044
dbSNP: rs761526509
Type: single nucleotide variant
Location: chr2:215326838 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 183: the 'imp cyclohydrolase' 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.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
ATIC c.-218A>G 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-ala183glu (accessed [today's date]).

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