# NM_206836.3(ECI2):c.74C>G (p.Pro25Arg)

https://sugi.bio/variant/eci2-p-pro25arg

## Summary

**ECI2 p.Pro25Arg (c.74C>G)** is classified **Uncertain significance** in ECI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-13). AlphaMissense: likely benign (0.0998); Ultra-rare (popmax 0.0174%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0174%, afr)

## For patients & families {#patients}

This is a change in the ECI2 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 | [ECI2](https://sugi.bio/atlas/gene/ECI2/) |
| Protein change (HGVS p.) | p.Pro25Arg |
| Coding change (HGVS c.) | c.74C>G |
| MANE Select transcript | [NM_206836](https://www.ncbi.nlm.nih.gov/nuccore/NM_206836) |
| Variant type | single nucleotide variant |
| Location | chr6:4133688-4133688 (GRCh38) |
| ClinVar | [VCV4246400](https://www.ncbi.nlm.nih.gov/clinvar/variation/4246400/) |

**All HGVS expressions:** `NC_000006.11:g.4133922G>C`, `NC_000006.12:g.4133688G>C`, `NM_001166010.2:c.-17C>G`, `NM_006117.3:c.-17C>G`, `NM_206836.3:c.74C>G`, `NR_028588.2:n.79C>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** (0.0998)
- REVEL 0.123 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.117 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.951, GERP -2.4, phastCons 0.6 — weakly conserved position
- CADD: **PHRED 12.02**. 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 0.99** across the covering region of the MANE Select transcript (4,115,877–4,135,560), spanning 19,683 bp. Chi-square p 0.84. 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 (G>T, Δ0.22 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 **0.0174%** (afr) · FAF95 0.0103% · FAF99 0.00813% · 13/74,858 in the highest group · 14/1,611,262 alleles overall — ultra-rare (popmax 0.0174%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0174% | 5,758 |
| Admixed American | 0.00168% | 59,444 |

*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}

**ECI2** population constraint: LOEUF 0.949, pLI 6.3048e-07, missense-Z 0.46659. *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 87.40, 73% of residues very-high.

**5 experimental structure(s)** (PDB): [2CQU](https://www.rcsb.org/structure/2CQU), [2F6Q](https://www.rcsb.org/structure/2F6Q), [4U18](https://www.rcsb.org/structure/4U18), [4U19](https://www.rcsb.org/structure/4U19), [4U1A](https://www.rcsb.org/structure/4U1A) — incl. mutant structure 4U19.

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

*Describes the biological roles of ECI2 (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:** ECI2's established molecular role includes delta(3)-delta(2)-enoyl-CoA isomerase activity.


### Pathways affected {#pathways}

ECI2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Beta-oxidation of very long chain fatty acids](https://reactome.org/content/detail/R-HSA-390247) | other |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | other |

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

**Molecular function:** delta(3)-delta(2)-enoyl-CoA isomerase activity.

**Biological process:** fatty acid catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-13.

**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 | 2025-07-13 |

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

## Similar variants {#similar}

Related ECI2 variant pages (same residue, condition, or type): [ECI2 p.Pro25Leu](/variant/eci2-p-pro25leu), [ECI2 p.Ala11Pro](/variant/eci2-p-ala11pro), [ECI2 p.Ala67Thr](/variant/eci2-p-ala67thr), [ECI2 p.Ala67Val](/variant/eci2-p-ala67val), [ECI2 p.Ala7Val](/variant/eci2-p-ala7val), [ECI2 p.Ala95Thr](/variant/eci2-p-ala95thr), [ECI2 p.Arg157Trp](/variant/eci2-p-arg157trp), [ECI2 p.Cys15Tyr](/variant/eci2-p-cys15tyr).

### 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 4246400). 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.*