# NM_004044.7(ATIC):c.131delinsGCA (p.Ala44fs)

https://sugi.bio/variant/atic-p-ala44fs

## Summary

**ATIC p.Ala44fs (c.131delinsGCA)** is classified **Conflicting classifications of pathogenicity** in ATIC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-18). No gnomAD frequency available for this variant; Associated with AICA-ribosiduria.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2105985030 · 3 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ATIC gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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.Ala44fs |
| Coding change (HGVS c.) | c.131delinsGCA |
| MANE Select transcript | [NM_004044](https://www.ncbi.nlm.nih.gov/nuccore/NM_004044) |
| dbSNP | [rs2105985030](https://www.ncbi.nlm.nih.gov/snp/rs2105985030/) |
| Variant type | Indel |
| Location | chr2:215312609-215312609 (GRCh38) |
| ClinVar | [VCV2439310](https://www.ncbi.nlm.nih.gov/clinvar/variation/2439310/) |

**All HGVS expressions:** `NC_000002.11:g.216177332delinsGCA`, `NC_000002.12:g.215312609delinsGCA`, `NG_013002.1:g.5654delinsGCA`, `NM_004044.7:c.131delinsGCA`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.766, GERP 2.09, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.044, pLI 4.8854e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 16**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **44** lies in the mgs-like domain; the 'imp cyclohydrolase' region; a turn.

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.Ala44fs 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-18.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Pathogenic).

**Submission history:** 3 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-18 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-01-15 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** AICA-ribosiduria, not provided, none provided, AICA-ribosiduria due to ATIC deficiency, 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 2439310). 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.*