CHAT p.Arg281=
c.843G>C · rs768892260 · VCV461464
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.033%, mid)
Conditions
1
congenital myasthenic syndrome 6
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.25 | acceptor gain · deltas |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 1.2 | GERP -2.6, phastCons 1 |
| Overall | ||
| CADD | 12.07 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.033%
Middle Eastern · 2/6,054 alleles
Filtering AF
0.00583%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00242%
Overall
0.000868%
14/1,612,750 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.033% | 3,027 |
| Admixed American | 0.00501% | 19,965 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,812 |
| European (non-Finnish) | 0.000509% | 196,600 |
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
- CHAT
- Protein
- p.Arg281=
- Coding
- c.843G>C
- MANE Select
- NM_020549
- dbSNP
- rs768892260
- Type
- single nucleotide variant
- Location
- chr10:49625563 (GRCh38)
- Gene constraint
- LOEUF 0.973 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 84.73 · 8 PDB
- Residue 281
- a β-strand
Similar variants
- CHAT p.Arg281Trp Likely pathogenic ★★ same residue
- SLC18A3 p.Pro281Ala Uncertain significance ★★ ⚠ same residue
- SLC18A3 p.Pro281= Likely benign ★ same residue
- SLC18A3 p.Pro281Leu Uncertain significance ⚠ same residue
- CHAT c.1282-2A>T Likely pathogenic ★★ same condition
- CHAT c.1840-9A>G Pathogenic/Likely pathogenic ★★ same condition
- CHAT c.698+1G>T Likely pathogenic ★★ same condition
- CHAT c.698+2T>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/chat-p-arg281 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown