# NM_001184.4(ATR):c.4988C>T (p.Thr1663Ile)

https://sugi.bio/variant/atr-p-thr1663ile

## Summary

**ATR p.Thr1663Ile (c.4988C>T)** is classified **Uncertain significance** in ATR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-23). AlphaMissense: likely benign (0.0703); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs984341860 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00401%, afr)

## For patients & families {#patients}

This is a change in the ATR gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [ATR](https://sugi.bio/atlas/gene/ATR/) |
| Protein change (HGVS p.) | p.Thr1663Ile |
| Coding change (HGVS c.) | c.4988C>T |
| MANE Select transcript | [NM_001184](https://www.ncbi.nlm.nih.gov/nuccore/NM_001184) |
| dbSNP | [rs984341860](https://www.ncbi.nlm.nih.gov/snp/rs984341860/) |
| Variant type | single nucleotide variant |
| Location | chr3:142507974-142507974 (GRCh38) |
| ClinVar | [VCV1744554](https://www.ncbi.nlm.nih.gov/clinvar/variation/1744554/) |

**All HGVS expressions:** `LRG_1403:g.75853C>T`, `LRG_1403t1:c.4988C>T`, `NC_000003.11:g.142226816G>A`, `NC_000003.12:g.142507974G>A`, `NG_008951.1:g.75853C>T`, `NM_001184.4:c.4988C>T`, `NM_001354579.2:c.4796C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0703)
- REVEL 0.036 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.737 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.527, GERP 0.825, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.99**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.26**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 43 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00401%** (afr) · FAF95 0.00107% · FAF99 0.000495% · 3/74,764 in the highest group · 4/1,613,144 alleles overall — very rare (popmax 0.00401%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00401% | 24,921 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,468 |

*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}

**ATR** population constraint: ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **GAPO syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 72.76, 38% of residues very-high.

**5 experimental structure(s)** (PDB): [3N2N](https://www.rcsb.org/structure/3N2N), [6ADL](https://www.rcsb.org/structure/6ADL), [6ADM](https://www.rcsb.org/structure/6ADM), [6ADR](https://www.rcsb.org/structure/6ADR), [6CX1](https://www.rcsb.org/structure/6CX1).

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

*Describes the biological roles of ATR (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:** ATR's established molecular role includes transmembrane signaling receptor activity. In Reactome, ATR is annotated in disease pathway(s) including **Uptake and function of anthrax toxins**.

**Disease mechanism (Reactome):** ATR loss or alteration is curated in [Uptake and function of anthrax toxins](https://reactome.org/content/detail/R-HSA-5210891).

### Pathways affected {#pathways}

ATR participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Uptake and function of anthrax toxins](https://reactome.org/content/detail/R-HSA-5210891) | other |

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

**Molecular function:** transmembrane signaling receptor activity, collagen binding, signaling receptor activity, actin filament binding.

**Biological process:** actin cytoskeleton organization, substrate adhesion-dependent cell spreading, positive regulation of epidermal growth factor receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-23.

**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 | 2021-11-23 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related ATR variant pages (same residue, condition, or type): [ANTXR1 p.Ala26Val](/variant/antxr1-p-ala26val), [ANTXR1 p.Arg444Gln](/variant/antxr1-p-arg444gln), [ANTXR1 p.Arg557Cys](/variant/antxr1-p-arg557cys), [ANTXR1 p.Gly369Ser](/variant/antxr1-p-gly369ser), [ANTXR1 p.Leu45Val](/variant/antxr1-p-leu45val), [ANTXR1 p.Pro524Leu](/variant/antxr1-p-pro524leu), [ANTXR1 p.Pro534Gln](/variant/antxr1-p-pro534gln), [ANTXR1 p.Thr503Asn](/variant/antxr1-p-thr503asn).

### 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 1744554). 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.*