Is ATIC p.Ala2Val (c.5C>T) pathogenic?

ATIC p.Ala2Val (c.5C>T) is classified Benign/Likely benign in ATIC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-02). AlphaMissense: likely benign (0.1768); Low-frequency (popmax 1.4%, afr); Associated with AICA-ribosiduria.

What condition is associated with ATIC p.Ala2Val (c.5C>T)?

ATIC p.Ala2Val (c.5C>T) is associated with AICA-ribosiduria, intellectual disability (ClinVar).

How common is ATIC p.Ala2Val (c.5C>T) in the general population?

ATIC p.Ala2Val (c.5C>T) is low-frequency (popmax 1.4%, afr) (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.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.1768) — an in-silico prediction, not a clinical call.

ATIC p.Ala2Val

c.5C>T · rs138988481 · VCV785991

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1768 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.4%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AICA-ribosiduria

Computational evidence

Protein change
AlphaMissense	0.1768	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 38 kb · p 0.044 · regional, not allelic
Overall
CADD	19.92	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 1.4% African / African-American · 995/71,260 alleles

Filtering AF 1.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.3%

Overall 0.0764% 1,164/1,524,312 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.4%	72
Middle Eastern	0.136%	735
Admixed American	0.125%	797
Remaining individualsnot grpmax-eligible	0.125%	803
South Asian	0.00243%	41,221
European (non-Finnish)	0.0021%	47,615

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_004044
dbSNP: rs138988481
Type: single nucleotide variant
Location: chr2:215312147 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 5 PDB
Residue 2: the mgs-like domain; the 'imp cyclohydrolase' 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

Also linked: intellectual disability

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-ala2val (accessed [today's date]).

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