# NM_003640.5(ELP1):c.1758T>G (p.Pro586=)

https://sugi.bio/variant/elp1-p-pro586

## Summary

**ELP1 p.Pro586= (c.1758T>G)** is classified **Benign/Likely benign** in ELP1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 6.09%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Riley-Day syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs35054425 · 9 submitters · 1 linked condition · common (popmax 6.09%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ELP1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 submitters, and is linked to Riley-Day syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 12 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ELP1 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Familial dysautonomia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Alacrima — Very frequent (99-80%)
- Abnormal pupil morphology — Very frequent (99-80%)
- Hypohidrosis — Very frequent (99-80%)
- Hyperhidrosis — Very frequent (99-80%)
- Hyporeflexia — Very frequent (99-80%)
- Orthostatic hypotension — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Malignant hyperthermia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007581/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ELP1](https://sugi.bio/atlas/gene/ELP1/) |
| Protein change (HGVS p.) | p.Pro586= |
| Coding change (HGVS c.) | c.1758T>G |
| MANE Select transcript | [NM_003640](https://www.ncbi.nlm.nih.gov/nuccore/NM_003640) |
| dbSNP | [rs35054425](https://www.ncbi.nlm.nih.gov/snp/rs35054425/) |
| Variant type | single nucleotide variant |
| Location | chr9:108902935-108902935 (GRCh38) |
| ClinVar | [VCV364572](https://www.ncbi.nlm.nih.gov/clinvar/variation/364572/) |

**All HGVS expressions:** `LRG_251:g.36394T>G`, `LRG_251t1:c.1758T>G`, `NC_000009.11:g.111665215A>C`, `NC_000009.12:g.108902935A>C`, `NG_008788.1:g.36394T>G`, `NM_001318360.2:c.1416T>G`, `NM_001330749.2:c.711T>G`, `NM_003640.5:c.1758T>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 6.09%, sas) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.018, GERP -3.18, phastCons 0.134 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.409**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **6.09%** (sas) · FAF95 5.95% · FAF99 5.9% · 5,541/91,008 in the highest group · 23,786/1,613,206 alleles overall — common (popmax 6.09%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 6.09% | 16 |
| Middle Eastern | 2.95% | 34 |
| Ashkenazi Jewish (not grpmax-eligible) | 2.29% | 44 |
| Remaining individuals (not grpmax-eligible) | 1.58% | 63 |
| European (non-Finnish) | 1.33% | 75 |
| Admixed American | 0.725% | 138 |
| African / African-American | 0.205% | 487 |
| Finnish (not grpmax-eligible) | 0.141% | 712 |
| East Asian | 0.0223% | 4,488 |

*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}

**ELP1** population constraint: LOEUF 0.803, pLI 1.1953e-23, missense-Z 0.98074. *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):

- **Riley-Day syndrome** — Moderate (AR)

## Protein context {#protein}

Residue **586** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 84.31, 49% of residues very-high.

**5 experimental structure(s)** (PDB): [5CQR](https://www.rcsb.org/structure/5CQR), [8PTX](https://www.rcsb.org/structure/8PTX), [8PTY](https://www.rcsb.org/structure/8PTY), [8PTZ](https://www.rcsb.org/structure/8PTZ), [8PU0](https://www.rcsb.org/structure/8PU0).

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

*Describes the biological roles of ELP1 (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}

ELP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (7 Benign, 2 Likely benign).

**Submission history:** 9 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2017-08-22 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2017-05-10 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-05-18 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-03-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2021-05-06 |

## Associated conditions {#conditions}

[Riley-Day syndrome](https://sugi.bio/atlas/disease/riley-day-syndrome/).

**Reported phenotype names (ClinVar):** Familial dysautonomia, not provided, not specified, none provided, AllHighlyPenetrant, HSAN III, FD.

## Similar variants {#similar}

Related ELP1 variant pages (same residue, condition, or type): [ELP1 c.1361-1G>T](/variant/elp1-c-1361-minus-1g-t), [ELP1 c.1361-2A>G](/variant/elp1-c-1361-minus-2a-g), [ELP1 c.1461-1G>A](/variant/elp1-c-1461-minus-1g-a), [ELP1 c.1644-1G>T](/variant/elp1-c-1644-minus-1g-t), [ELP1 c.1644-2A>C](/variant/elp1-c-1644-minus-2a-c), [ELP1 c.1854+1G>A](/variant/elp1-c-1854-plus-1g-a), [ELP1 c.2015-2A>G](/variant/elp1-c-2015-minus-2a-g), [ELP1 c.2204+6T>C](/variant/elp1-c-2204-plus-6t-c).

### 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 364572). 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.*