# NM_001077706.3(ECT2L):c.452A>G (p.His151Arg)

https://sugi.bio/variant/ect2l-p-his151arg

## Summary

**ECT2L p.His151Arg (c.452A>G)** is classified **Uncertain significance** in ECT2L (ClinVar, Single submitter, 2 submitters; last evaluated 2025-02-04). AlphaMissense: likely benign (0.1054); Very rare (popmax 0.00133%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs587778243 · 2 submitters · AlphaMissense likely benign · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the ECT2L gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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 | [ECT2L](https://sugi.bio/atlas/gene/ECT2L/) |
| Protein change (HGVS p.) | p.His151Arg |
| Coding change (HGVS c.) | c.452A>G |
| MANE Select transcript | [NM_001077706](https://www.ncbi.nlm.nih.gov/nuccore/NM_001077706) |
| dbSNP | [rs587778243](https://www.ncbi.nlm.nih.gov/snp/rs587778243/) |
| Variant type | single nucleotide variant |
| Location | chr6:138843088-138843088 (GRCh38) |
| ClinVar | [VCV134007](https://www.ncbi.nlm.nih.gov/clinvar/variation/134007/) |

**All HGVS expressions:** `NC_000006.11:g.139164225A>G`, `NC_000006.12:g.138843088A>G`, `NM_001077706.2:c.452A>G`, `NM_001077706.3:c.452A>G`, `NM_001195037.2:c.452A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1054)
- REVEL 0.185 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.185 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -2.375, GERP -4.64 — fast-evolving / accelerated position
- CADD: **PHRED 4.276**. 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 0.95** across the covering region of the MANE Select transcript (138,813,275–138,902,624), spanning 89,349 bp. Chi-square p 0.11. 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>C, Δ0.44 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 **0.00133%** (afr) · 1/75,034 in the highest group · 1/1,461,794 alleles overall — very rare (popmax 0.00133%, afr).

*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}

**ECT2L** population constraint: LOEUF 1.127, pLI 6.6862e-35, missense-Z 0.99586. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.75, 22% of residues very-high.

**1 experimental structure(s)** (PDB): [11XU](https://www.rcsb.org/structure/11XU).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-04.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 not provided).

**Submission history:** 2 submissions (2013–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-04 |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |

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

## Similar variants {#similar}

Related ECT2L variant pages (same residue, condition, or type): [ECT2L p.Ala147Thr](/variant/ect2l-p-ala147thr), [ECT2L p.Ala161Thr](/variant/ect2l-p-ala161thr), [ECT2L p.Ala299Val](/variant/ect2l-p-ala299val), [ECT2L p.Ala401Ser](/variant/ect2l-p-ala401ser), [ECT2L p.Ala443Ser](/variant/ect2l-p-ala443ser), [ECT2L p.Ala515Gly](/variant/ect2l-p-ala515gly), [ECT2L p.Ala599Thr](/variant/ect2l-p-ala599thr), [ECT2L p.Ala605Gly](/variant/ect2l-p-ala605gly).

### 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 134007). 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.*