Is ATIC p.His584Arg (c.1751A>G) pathogenic?

ATIC p.His584Arg (c.1751A>G) is classified Uncertain significance in ATIC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-02). AlphaMissense: ambiguous (0.4588); Rare (popmax 0.445%, mid); Associated with AICA-ribosiduria.

What condition is associated with ATIC p.His584Arg (c.1751A>G)?

ATIC p.His584Arg (c.1751A>G) is associated with AICA-ribosiduria (ClinVar).

How common is ATIC p.His584Arg (c.1751A>G) in the general population?

ATIC p.His584Arg (c.1751A>G) is rare (popmax 0.445%, 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.His584Arg (c.1751A>G)?

AlphaMissense predicts ambiguous (score 0.4588) — an in-silico prediction, not a clinical call.

ATIC p.His584Arg

c.1751A>G · rs201429123 · VCV548528

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4588 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.445%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

AICA-ribosiduria

Computational evidence

Protein change
AlphaMissense	0.4588	ambiguous
REVEL	0.673	pathogenic-leaning
SaProt	LLR -10.95	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	23.6	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 0.445% Middle Eastern · 27/6,062 alleles

Filtering AF 0.314% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.27%

Overall 0.0116% 188/1,614,192 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.445%	225
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Admixed American	0.0217%	4,617
South Asian	0.0143%	7,006
European (non-Finnish)	0.00907%	11,028
African / African-American	0.00267%	37,523

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.His584Arg
Coding: c.1751A>G
MANE Select: NM_004044
dbSNP: rs201429123
Type: single nucleotide variant
Location: chr2:215349627 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 584: the 'aicar formyltransferase' region; a β-strand

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 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-his584arg (accessed [today's date]).

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