Is ELP1 p.Arg696Pro (c.2087G>C) pathogenic?

ELP1 p.Arg696Pro (c.2087G>C) is classified Pathogenic/Likely pathogenic in ELP1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-07-21). AlphaMissense: likely pathogenic (0.9811); Very rare (popmax 0.000274%); Associated with Riley-Day syndrome.

What condition is associated with ELP1 p.Arg696Pro (c.2087G>C)?

ELP1 p.Arg696Pro (c.2087G>C) is associated with Riley-Day syndrome, medulloblastoma, Charcot-Marie-Tooth disease (ClinVar).

How common is ELP1 p.Arg696Pro (c.2087G>C) in the general population?

ELP1 p.Arg696Pro (c.2087G>C) is very rare (popmax 0.000274%) (gnomAD).

How is Familial dysautonomia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ELP1 p.Arg696Pro (c.2087G>C)?

AlphaMissense predicts likely pathogenic (score 0.9811) — an in-silico prediction, not a clinical call.

ELP1 p.Arg696Pro

c.2087G>C · rs137853022 · VCV6086

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000274%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Riley-Day syndrome

Computational evidence

Protein change
AlphaMissense	0.9811	likely pathogenic ✓ concordant with ClinVar · top 1% in ELP1
REVEL	0.539	indeterminate
SaProt	LLR -16.86	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000274%

Overall 0.000274% 4/1,461,856 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Remaining individualsnot grpmax-eligible	0.0016%	62,508

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ELP1
Protein: p.Arg696Pro
Coding: c.2087G>C
MANE Select: NM_003640
dbSNP: rs137853022
Type: single nucleotide variant
Location: chr9:108900303 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 5 PDB
Residue 696: a β-strand; a UniProt-annotated variant site (in fd; mild phenotype; phosphorylation is reduced; does not affect interaction with elp2; reduced interaction with elp3; does not affect dimerization)

Full ELP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Riley-Day syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: medulloblastoma Charcot-Marie-Tooth disease

For Familial dysautonomia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

ELP1 p.Arg696Gln Uncertain significance ★★ ⚠ same residue
ELP1 p.Arg696Trp Uncertain significance ★ ⚠ same residue
ELP1 p.Arg696= Likely benign ★ same residue
ELP1 c.1361-1G>T Pathogenic/Likely pathogenic ★★ same condition
ELP1 c.1361-2A>G Pathogenic/Likely pathogenic ★★ same condition
ELP1 c.1461-1G>A Likely pathogenic ★★ same condition
ELP1 c.1644-1G>T Likely pathogenic ★★ same condition
ELP1 c.1644-2A>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/elp1-p-arg696pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown