Is CHAT p.Arg117His (c.350G>A) pathogenic?

CHAT p.Arg117His (c.350G>A) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0792); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with CHAT p.Arg117His (c.350G>A)?

CHAT p.Arg117His (c.350G>A) is associated with Inborn genetic diseases, congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg117His (c.350G>A) in the general population?

CHAT p.Arg117His (c.350G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CHAT p.Arg117His (c.350G>A)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

CHAT p.Arg117His

c.350G>A · rs376641216 · VCV844096

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.094	GERP -3.7
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	9.089	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00118% 19/1,612,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00667%	14,990
African / African-American	0.004%	24,991
East Asian	0.00223%	44,826
South Asian	0.0022%	45,404
European (non-Finnish)	0.000678%	147,418

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.Arg117His
Coding: c.350G>A
MANE Select: NM_020549
dbSNP: rs376641216
Type: single nucleotide variant
Location: chr10:49616565 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.73 · 8 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 6

Similar variants

SLC18A3 p.Thr117Met Uncertain significance ★ ⚠ same residue
CHAT p.Arg117Cys Likely benign ★ ⚠ same residue
CHAT p.Arg117fs Conflicting classifications of pathogenicity ★ same residue
SLC18A3 p.Thr117= Likely benign ★ 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-arg117his (accessed [today's date]).

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