# NM_001258315.2(ECT2):c.2107A>T (p.Ile703Leu)

https://sugi.bio/variant/ect2-p-ile703leu

## Summary

**ECT2 p.Ile703Leu (c.2107A>T)** is classified **Uncertain significance** in ECT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-27). AlphaMissense: likely benign (0.2485); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2475083616 · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ECT2 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 | [ECT2](https://sugi.bio/atlas/gene/ECT2/) |
| Protein change (HGVS p.) | p.Ile703Leu |
| Coding change (HGVS c.) | c.2107A>T |
| MANE Select transcript | [NM_001258315](https://www.ncbi.nlm.nih.gov/nuccore/NM_001258315) |
| dbSNP | [rs2475083616](https://www.ncbi.nlm.nih.gov/snp/rs2475083616/) |
| Variant type | single nucleotide variant |
| Location | chr3:172805731-172805731 (GRCh38) |
| ClinVar | [VCV2321438](https://www.ncbi.nlm.nih.gov/clinvar/variation/2321438/) |

**All HGVS expressions:** `NC_000003.11:g.172523521A>T`, `NC_000003.12:g.172805731A>T`, `NM_001258315.2:c.2107A>T`, `NM_001258316.2:c.2014A>T`, `NM_001349094.2:c.2107A>T`, `NM_001349095.2:c.2107A>T`, `NM_001349096.2:c.2107A>T`, `NM_001349097.2:c.2104A>T`, `NM_001349098.2:c.2107A>T`, `NM_001349099.2:c.2107A>T`, `NM_001349100.2:c.2107A>T`, `NM_001349101.2:c.2014A>T`, `NM_001349102.2:c.2011A>T`, `NM_001349103.2:c.1927A>T`, `NM_001349104.2:c.1927A>T`, `NM_018098.6:c.2014A>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** (0.2485)
- REVEL 0.126 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.669 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.42) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.132, GERP 0.755, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.9**. 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 0.87** across the covering region of the MANE Select transcript (172,754,531–172,820,234), spanning 65,703 bp. Chi-square p 1.6e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.42**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss at this position.
- 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.*
- Pangolin: Δ**0.25** (loss), gain 0.03 / loss 0.25. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ECT2** population constraint: LOEUF 0.664, pLI 0.00015403, missense-Z 1.9037. *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 **703** lies in a β-strand; the ph domain.

AlphaFold model confidence (whole protein): pLDDT 71.17, 27% of residues very-high.

**3 experimental structure(s)** (PDB): [3L46](https://www.rcsb.org/structure/3L46), [4N40](https://www.rcsb.org/structure/4N40), [6L30](https://www.rcsb.org/structure/6L30).

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

*Describes the biological roles of ECT2 (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:** ECT2's established molecular role includes guanyl-nucleotide exchange factor activity. p.Ile703Leu falls in the ph domain.


### Pathways affected {#pathways}

ECT2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [G alpha (12/13) signalling events](https://reactome.org/content/detail/R-HSA-416482) | curated |
| [NRAGE signals death through JNK](https://reactome.org/content/detail/R-HSA-193648) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | curated |

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

**Molecular function:** guanyl-nucleotide exchange factor activity, GTPase activator activity, protein homodimerization activity.

**Biological process:** mitotic cytokinesis, activation of protein kinase activity, positive regulation of cytokinesis, positive regulation of apoptotic process, positive regulation of GTPase activity, regulation of protein kinase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-27.

**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 | 2022-10-27 |

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

## Similar variants {#similar}

Related ECT2 variant pages (same residue, condition, or type): [ECT2 p.His912Arg](/variant/ect2-p-his912arg), [ECT2 p.Pro236Ala](/variant/ect2-p-pro236ala), [ECT2 p.Pro481=](/variant/ect2-p-pro481), [ECT2 c.1069-2A>G](/variant/ect2-c-1069-minus-2a-g), [ECT2 p.Ala258Thr](/variant/ect2-p-ala258thr), [ECT2 p.Ala850Thr](/variant/ect2-p-ala850thr), [ECT2 p.Arg169Cys](/variant/ect2-p-arg169cys), [ECT2 p.Arg194Met](/variant/ect2-p-arg194met).

### 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 2321438). 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.*