# NM_000501.4(ELN):c.1999C>T (p.Pro667Ser)

https://sugi.bio/variant/eln-p-pro667ser

## Summary

**ELN p.Pro667Ser (c.1999C>T)** is classified **Conflicting classifications of pathogenicity** in ELN (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0426); Low-frequency (popmax 1.58%, mid); Associated with supravalvular aortic stenosis.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs142316834 · 10 submitters · 4 linked conditions · AlphaMissense likely benign · low-frequency (popmax 1.58%, mid)

## For patients & families {#patients}

This is a change in the ELN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 10 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.Pro667Ser |
| Coding change (HGVS c.) | c.1999C>T |
| MANE Select transcript | [NM_000501](https://www.ncbi.nlm.nih.gov/nuccore/NM_000501) |
| dbSNP | [rs142316834](https://www.ncbi.nlm.nih.gov/snp/rs142316834/) |
| Variant type | single nucleotide variant |
| Location | chr7:74065699-74065699 (GRCh38) |
| ClinVar | [VCV213166](https://www.ncbi.nlm.nih.gov/clinvar/variation/213166/) |

**All HGVS expressions:** `NC_000007.13:g.73480029C>T`, `NC_000007.14:g.74065699C>T`, `NG_009261.1:g.42603C>T`, `NM_000501.4:c.1999C>T`, `NM_001081752.3:c.1912C>T`, `NM_001081753.3:c.1957C>T`, `NM_001081754.3:c.2014C>T`, `NM_001081755.3:c.1942C>T`, `NM_001278912.2:c.1999C>T`, `NM_001278913.2:c.1756C>T`, `NM_001278914.2:c.1927C>T`, `NM_001278915.2:c.2017C>T`, `NM_001278916.2:c.1855C>T`, `NM_001278917.2:c.1969C>T`, `NM_001278918.2:c.1732C>T`, `NM_001278939.2:c.2185C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0426)
- REVEL 0.024 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -2.511 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.034, GERP 4.58, phastCons 0.874 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P729S** vs ClinVar **P667S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 12.21**. 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>G, Δ0.23 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 **1.58%** (mid) · FAF95 1.33% · FAF99 1.23% · 96/6,062 in the highest group · 563/1,613,806 alleles overall — low-frequency (popmax 1.58%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 1.58% | 63 |
| Remaining individuals (not grpmax-eligible) | 0.08% | 1,250 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0574% | 1,741 |
| South Asian | 0.0527% | 1,897 |
| African / African-American | 0.044% | 2,270 |
| Admixed American | 0.0433% | 2,307 |
| European (non-Finnish) | 0.0248% | 4,027 |

*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 3/3, triplosensitivity 0/3. *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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (7 Likely benign, 2 Benign, 1 Uncertain significance, 1 not provided).

**Submission history:** 11 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-09-17 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-06-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-27 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-08 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |

## Associated conditions {#conditions}

[supravalvular aortic stenosis](https://sugi.bio/atlas/disease/supravalvular-aortic-stenosis/), [cutis laxa, autosomal dominant 1](https://sugi.bio/atlas/disease/cutis-laxa-autosomal-dominant-1/), [Williams syndrome](https://sugi.bio/atlas/disease/williams-syndrome/), [autosomal dominant cutis laxa](https://sugi.bio/atlas/disease/autosomal-dominant-cutis-laxa/).

**Reported phenotype names (ClinVar):** Supravalvar aortic stenosis, Cutis laxa, autosomal dominant 1, not provided, ELN-related disorder, Cutis laxa, autosomal dominant, Williams syndrome, not specified, Supravalvar aortic stenosis, Eisenberg type, WILLIAMS-BEUREN SYNDROME, CHROMOSOME 7q11.23 DELETION SYNDROME, 1.5- TO 1.8-MB.

## Similar variants {#similar}

Related ELN variant pages (same residue, condition, or type): [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), [ELN c.889+1G>A](/variant/eln-c-889-plus-1g-a).

### 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 213166). 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.*