Is CHAT p.Arg628Gln (c.1883G>A) pathogenic?

CHAT p.Arg628Gln (c.1883G>A) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1897); Ultra-rare (popmax 0.0913%, nfe); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Arg628Gln (c.1883G>A)?

CHAT p.Arg628Gln (c.1883G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Arg628Gln (c.1883G>A) in the general population?

CHAT p.Arg628Gln (c.1883G>A) is ultra-rare (popmax 0.0913%, nfe) (gnomAD).

What do computational predictors say about CHAT p.Arg628Gln (c.1883G>A)?

AlphaMissense predicts likely benign (score 0.1897) — an in-silico prediction, not a clinical call.

CHAT p.Arg628Gln

c.1883G>A · rs114545628 · VCV194422

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1897 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0913%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.1897	likely benign
REVEL	0.761	pathogenic-leaning
SaProt	LLR -7.73	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	29.2	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 0.0913% European (non-Finnish) · 1,077/1,180,024 alleles

Filtering AF 0.0867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0849%

Overall 0.0696% 1,124/1,614,188 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0913%	1,096
Remaining individualsnot grpmax-eligible	0.0384%	2,605
Middle Eastern	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,402
African / African-American	0.0133%	7,505
Admixed American	0.00333%	30,012
South Asian	0.00329%	30,361
Finnishnot grpmax-eligible	0.00312%	32,021
East Asian	0.00223%	44,876

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.Arg628Gln
Coding: c.1883G>A
MANE Select: NM_020549
dbSNP: rs114545628
Type: single nucleotide variant
Location: chr10:49662688 (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 628: an α-helix

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

Disease context

congenital myasthenic syndrome 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHAT p.Arg628Trp Uncertain significance ★★ ⚠ same residue
CHAT p.Arg628= 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
CHAT p.Ala557Thr Pathogenic/Likely pathogenic ★★ same condition
CHAT p.Arg151Ter Pathogenic/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-arg628gln (accessed [today's date]).

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