# NM_004044.7(ATIC):c.1443A>G (p.Gly481=)

https://sugi.bio/variant/atic-p-gly481

## Summary

**ATIC p.Gly481= (c.1443A>G)** is classified **Benign** in ATIC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-19). Low-frequency (popmax 2.8%, nfe).

**At a glance:** Benign · review: Multiple submitters · rsID rs112288749 · 3 submitters · low-frequency (popmax 2.8%, nfe)

## For patients & families {#patients}

This is a change in the ATIC gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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.*

**Support & next steps:** [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.Gly481= |
| Coding change (HGVS c.) | c.1443A>G |
| MANE Select transcript | [NM_004044](https://www.ncbi.nlm.nih.gov/nuccore/NM_004044) |
| dbSNP | [rs112288749](https://www.ncbi.nlm.nih.gov/snp/rs112288749/) |
| Variant type | single nucleotide variant |
| Location | chr2:215346881-215346881 (GRCh38) |
| ClinVar | [VCV1600148](https://www.ncbi.nlm.nih.gov/clinvar/variation/1600148/) |

**All HGVS expressions:** `NC_000002.11:g.216211604A>G`, `NC_000002.12:g.215346881A>G`, `NG_013002.1:g.39926A>G`, `NM_004044.7:c.1443A>G`

## 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 -0.049, GERP -4.77, phastCons 0.04 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.003**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.28 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **2.8%** (nfe) · FAF95 2.78% · FAF99 2.77% · 33,090/1,180,026 in the highest group · 37,422/1,614,178 alleles overall — low-frequency (popmax 2.8%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 2.8% | 36 |
| Finnish (not grpmax-eligible) | 2.51% | 40 |
| Remaining individuals (not grpmax-eligible) | 1.9% | 53 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.11% | 90 |
| Admixed American | 0.846% | 118 |
| Middle Eastern | 0.775% | 129 |
| African / African-American | 0.401% | 249 |
| South Asian | 0.382% | 262 |
| East Asian | 0.00668% | 14,962 |

*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 **481** lies in the 'aicar formyltransferase' 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.Gly481= falls in the aicar formyltransferase region. 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** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 88 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-19 |

**Reported phenotype names (ClinVar):** not provided, Thymoma, Thyroid cancer, nonmedullary, 1, Melanoma, Acute myeloid leukemia, Uterine corpus endometrial carcinoma, Uveal melanoma, Germ cell tumor of testis, Lung cancer, Cervical cancer.

## Similar variants {#similar}

Related ATIC variant pages (same residue, condition, or type): [ATIC c.688+3A>G](/variant/atic-c-688-plus-3a-g), [ATIC p.Ala140Thr](/variant/atic-p-ala140thr), [ATIC p.Ala183Glu](/variant/atic-p-ala183glu), [ATIC p.Ala510Thr](/variant/atic-p-ala510thr), [ATIC p.His584Arg](/variant/atic-p-his584arg), [ATIC p.Ile491Val](/variant/atic-p-ile491val), [ATIC p.Val154Ala](/variant/atic-p-val154ala), [FN1 p.Ala2470Pro](/variant/fn1-p-ala2470pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1600148). 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.*