# NM_001258315.2(ECT2):c.2023C>T (p.Arg675Trp)

https://sugi.bio/variant/ect2-p-arg675trp

## Summary

**ECT2 p.Arg675Trp (c.2023C>T)** is classified **Uncertain significance** in ECT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-26). AlphaMissense: likely pathogenic (0.6046); Very rare (popmax 0.00668%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1365878389 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00668%, afr)

## 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.Arg675Trp |
| Coding change (HGVS c.) | c.2023C>T |
| MANE Select transcript | [NM_001258315](https://www.ncbi.nlm.nih.gov/nuccore/NM_001258315) |
| dbSNP | [rs1365878389](https://www.ncbi.nlm.nih.gov/snp/rs1365878389/) |
| Variant type | single nucleotide variant |
| Location | chr3:172802897-172802897 (GRCh38) |
| ClinVar | [VCV2551982](https://www.ncbi.nlm.nih.gov/clinvar/variation/2551982/) |

**All HGVS expressions:** `NC_000003.11:g.172520687C>T`, `NC_000003.12:g.172802897C>T`, `NM_001258315.2:c.2023C>T`, `NM_001258316.2:c.1930C>T`, `NM_001349094.2:c.2023C>T`, `NM_001349095.2:c.2023C>T`, `NM_001349096.2:c.2023C>T`, `NM_001349097.2:c.2020C>T`, `NM_001349098.2:c.2023C>T`, `NM_001349099.2:c.2023C>T`, `NM_001349100.2:c.2023C>T`, `NM_001349101.2:c.1930C>T`, `NM_001349102.2:c.1927C>T`, `NM_001349103.2:c.1843C>T`, `NM_001349104.2:c.1843C>T`, `NM_018098.6:c.1930C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6046)
- REVEL 0.333 (indeterminate)
- SaProt LLR -16.236 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- SpliceAI predicts **acceptor loss** (Δ 0.32) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.57, GERP 1.09, phastCons 0.039 — weakly conserved position
- CADD: **PHRED 20.7**. 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 **0.32**, donor loss **0.23**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 36 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.*
- Pangolin: Δ**0.33** (loss), gain 0.02 / loss 0.33. 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 (gnomAD v4.1): grpmax **0.00668%** (afr) · FAF95 0.00255% · FAF99 0.00162% · 5/74,868 in the highest group · 18/1,612,918 alleles overall — very rare (popmax 0.00668%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00668% | 14,974 |
| East Asian | 0.00223% | 44,754 |
| South Asian | 0.0011% | 91,036 |
| European (non-Finnish) | 0.000933% | 107,217 |

*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 **675** 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.Arg675Trp 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 2023-05-26.

**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 | 2023-05-26 |

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

## Similar variants {#similar}

Related ECT2 variant pages (same residue, condition, or type): [ECT2 p.Arg675Gln](/variant/ect2-p-arg675gln), [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).

### 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 2551982). 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.*