# NM_004044.7(ATIC):c.5C>T (p.Ala2Val)

https://sugi.bio/variant/atic-p-ala2val

## Summary

**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.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs138988481 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · low-frequency (popmax 1.4%, afr)

## For patients & families {#patients}

This is a change in the ATIC gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to AICA-ribosiduria.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ATIC is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of AICA-ribosiduria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Fused labia minora — Very frequent (99-80%)
- Wide mouth — Very frequent (99-80%)
- Thin upper lip vermilion — Very frequent (99-80%)
- Brachycephaly — Very frequent (99-80%)
- Low-set ears — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Congenital blindness — Very frequent (99-80%)
- Clitoral hypertrophy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013781/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ATIC](https://sugi.bio/atlas/gene/ATIC/) |
| Protein change (HGVS p.) | p.Ala2Val |
| Coding change (HGVS c.) | c.5C>T |
| MANE Select transcript | [NM_004044](https://www.ncbi.nlm.nih.gov/nuccore/NM_004044) |
| dbSNP | [rs138988481](https://www.ncbi.nlm.nih.gov/snp/rs138988481/) |
| Variant type | single nucleotide variant |
| Location | chr2:215312147-215312147 (GRCh38) |
| ClinVar | [VCV785991](https://www.ncbi.nlm.nih.gov/clinvar/variation/785991/) |

**All HGVS expressions:** `NC_000002.11:g.216176870C>T`, `NC_000002.12:g.215312147C>T`, `NG_013002.1:g.5192C>T`, `NM_004044.7:c.5C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1768)
- REVEL 0.101 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.02 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.137, GERP 1.83, phastCons 0.997 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.92**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.07** across the covering region of the MANE Select transcript (215,312,143–215,349,652), spanning 37,509 bp. Chi-square p 0.044. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **1.4%** (afr) · FAF95 1.32% · FAF99 1.3% · 995/71,260 in the highest group · 1,164/1,524,312 alleles overall — low-frequency (popmax 1.4%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.4% | 72 |
| Middle Eastern | 0.136% | 735 |
| Admixed American | 0.125% | 797 |
| Remaining individuals (not grpmax-eligible) | 0.125% | 803 |
| South Asian | 0.00243% | 41,221 |
| European (non-Finnish) | 0.0021% | 47,615 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ATIC** population constraint: LOEUF 1.044, pLI 4.8854e-17, missense-Z -0.26716. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **2** lies in the mgs-like domain; the 'imp cyclohydrolase' region.

AlphaFold model confidence (whole protein): pLDDT 97.46, 99% of residues very-high.

**5 experimental structure(s)** (PDB): [1P4R](https://www.rcsb.org/structure/1P4R), [1PKX](https://www.rcsb.org/structure/1PKX), [1PL0](https://www.rcsb.org/structure/1PL0), [5UY8](https://www.rcsb.org/structure/5UY8), [5UZ0](https://www.rcsb.org/structure/5UZ0).

## What this gene does {#gene-function}

*Describes the biological roles of ATIC (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ATIC's established molecular role includes IMP cyclohydrolase activity. p.Ala2Val falls in the mgs-like domain. In Reactome, ATIC is annotated in disease pathway(s) including **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** ATIC loss or alteration is curated in [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370).

### Pathways affected {#pathways}

ATIC participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [Purine ribonucleoside monophosphate biosynthesis](https://reactome.org/content/detail/R-HSA-73817) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** IMP cyclohydrolase activity, protein homodimerization activity, cadherin binding.

**Biological process:** GMP biosynthetic process, 'de novo' IMP biosynthetic process, 'de novo' AMP biosynthetic process, 'de novo' XMP biosynthetic process.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-02.

**Submitter consensus:** conflicting (3 Likely benign, 2 Benign).

**Submission history:** 5 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Likely benign | no assertion criteria provided | clinical testing | 2019-01-01 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-20 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-04-02 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-20 |

## Associated conditions {#conditions}

[AICA-ribosiduria](https://sugi.bio/atlas/disease/aica-ribosiduria/), [intellectual disability](https://sugi.bio/atlas/disease/intellectual-disability/).

**Reported phenotype names (ClinVar):** AICA-ribosiduria, not provided, Intellectual disability, not specified, Intellectual functioning disability, intellectual disabilities, Intellectual developmental disorder, AllHighlyPenetrant, ATIC DEFICIENCY, AICA-ribosiduria due to ATIC deficiency.

## Similar variants {#similar}

Related ATIC variant pages (same residue, condition, or type): [ATIC p.Ala183Glu](/variant/atic-p-ala183glu), [ATIC p.His584Arg](/variant/atic-p-his584arg), [ATIC c.1098+60C>G](/variant/atic-c-1098-plus-60c-g), [ATIC c.1228-30A>G](/variant/atic-c-1228-minus-30a-g), [ATIC c.147-111A>T](/variant/atic-c-147-minus-111a-t), [ATIC c.1503+48A>T](/variant/atic-c-1503-plus-48a-t), [ATIC c.380-18G>A](/variant/atic-c-380-minus-18g-a), [ATIC c.380-19A>C](/variant/atic-c-380-minus-19a-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 785991). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*