# NM_004044.7(ATIC):c.1363A>G (p.Thr455Ala)

https://sugi.bio/variant/atic-p-thr455ala

## Summary

**ATIC p.Thr455Ala (c.1363A>G)** is classified **Uncertain significance** in ATIC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: ambiguous (0.5368); Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the ATIC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.Thr455Ala |
| Coding change (HGVS c.) | c.1363A>G |
| MANE Select transcript | [NM_004044](https://www.ncbi.nlm.nih.gov/nuccore/NM_004044) |
| Variant type | single nucleotide variant |
| Location | chr2:215346801-215346801 (GRCh38) |
| ClinVar | [VCV3961791](https://www.ncbi.nlm.nih.gov/clinvar/variation/3961791/) |

**All HGVS expressions:** `NC_000002.11:g.216211524A>G`, `NC_000002.12:g.215346801A>G`, `NG_013002.1:g.39846A>G`, `NM_004044.7:c.1363A>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5368) — no call either way
- REVEL 0.73 (pathogenic-leaning)
- SaProt LLR -10.489 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 11.149, GERP 2.86, phastCons 1 — highly conserved
- CADD: **PHRED 26.3**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.20 acceptor 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 **0.0165%** (mid) · FAF95 0.00286% · FAF99 0.00195% · 1/6,062 in the highest group · 11/1,614,168 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| South Asian | 0.00659% | 15,181 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,627 |

*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 **455** lies in the 'aicar formyltransferase' region; an α-helix.

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.Thr455Ala 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-17.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-17 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ATIC variant pages (same residue, condition, or type): [ATIC p.Thr455Pro](/variant/atic-p-thr455pro), [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).

### 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 3961791). 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.*