# NM_000501.4(ELN):c.2109C>G (p.Phe703Leu)

https://sugi.bio/variant/eln-p-phe703leu

## Summary

**ELN p.Phe703Leu (c.2109C>G)** is classified **Uncertain significance** in ELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-30). AlphaMissense: likely pathogenic (0.902); Very rare (popmax 0.00017%, nfe); Associated with supravalvular aortic stenosis.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs149755814 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the ELN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to supravalvular aortic stenosis.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000743/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ELN](https://sugi.bio/atlas/gene/ELN/) |
| Protein change (HGVS p.) | p.Phe703Leu |
| Coding change (HGVS c.) | c.2109C>G |
| MANE Select transcript | [NM_000501](https://www.ncbi.nlm.nih.gov/nuccore/NM_000501) |
| dbSNP | [rs149755814](https://www.ncbi.nlm.nih.gov/snp/rs149755814/) |
| Variant type | single nucleotide variant |
| Location | chr7:74066754-74066754 (GRCh38) |
| ClinVar | [VCV1413338](https://www.ncbi.nlm.nih.gov/clinvar/variation/1413338/) |

**All HGVS expressions:** `NC_000007.13:g.73481084C>G`, `NC_000007.14:g.74066754C>G`, `NG_009261.1:g.43658C>G`, `NM_000501.2:c.2109C>G`, `NM_000501.4:c.2109C>G`, `NM_001081752.3:c.1968C>G`, `NM_001081753.3:c.2013C>G`, `NM_001081754.3:c.2070C>G`, `NM_001081755.3:c.2052C>G`, `NM_001278912.2:c.2055C>G`, `NM_001278913.2:c.1866C>G`, `NM_001278914.2:c.2037C>G`, `NM_001278915.2:c.2127C>G`, `NM_001278916.2:c.1911C>G`, `NM_001278917.2:c.2079C>G`, `NM_001278918.2:c.1788C>G`, `NM_001278939.2:c.2295C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.902)
- REVEL 0.212 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -5.218 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP -2.981, GERP -6.47 — fast-evolving / accelerated position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **F765L** vs ClinVar **F703L**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in ELN (of 4,436 modeled).
- CADD: **PHRED 6.373**. 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 0.91** across the covering region of the MANE Select transcript (74,028,188–74,068,697), spanning 40,509 bp. Chi-square p 0.005. 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 (C>A, Δ0.36 donor loss), 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 **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,684 in the highest group · 2/1,461,406 alleles overall — very rare (popmax 0.00017%, nfe).

*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}

**ELN** population constraint: LOEUF 0.696, pLI 7.6169e-10, missense-Z 1.2583; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **cutis laxa, autosomal dominant 1** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 36.20, 0% of residues very-high.

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

*Describes the biological roles of ELN (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.*


### Pathways affected {#pathways}

ELN participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |
| [Elastic fibre formation](https://reactome.org/content/detail/R-HSA-1566948) | curated |
| [Molecules associated with elastic fibres](https://reactome.org/content/detail/R-HSA-2129379) | electronic |

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

**Biological process:** outflow tract morphogenesis.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-30.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-27 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-30 |

## Associated conditions {#conditions}

[supravalvular aortic stenosis](https://sugi.bio/atlas/disease/supravalvular-aortic-stenosis/).

**Reported phenotype names (ClinVar):** Supravalvar aortic stenosis, Inborn genetic diseases, Supravalvar aortic stenosis, Eisenberg type.

## Similar variants {#similar}

Related ELN variant pages (same residue, condition, or type): [ELN p.Phe703=](/variant/eln-p-phe703), [ELN c.377-2A>G](/variant/eln-c-377-minus-2a-g), [ELN c.643+1G>C](/variant/eln-c-643-plus-1g-c), [ELN c.686-2A>G](/variant/eln-c-686-minus-2a-g), [ELN c.800-1G>A](/variant/eln-c-800-minus-1g-a), [ELN c.800-2A>G](/variant/eln-c-800-minus-2a-g), [ELN c.800-3C>G](/variant/eln-c-800-minus-3c-g), [ELN c.82+1G>A](/variant/eln-c-82-plus-1g-a).

### 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 1413338). 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.*