Is CHAT p.Met202Arg (c.605T>G) pathogenic?

CHAT p.Met202Arg (c.605T>G) is classified Pathogenic/Likely pathogenic in CHAT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-18). AlphaMissense: likely pathogenic (0.7382); Rare (popmax 0.105%, afr); Associated with congenital myasthenic syndrome.

What condition is associated with CHAT p.Met202Arg (c.605T>G)?

CHAT p.Met202Arg (c.605T>G) is associated with congenital myasthenic syndrome, congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Met202Arg (c.605T>G) in the general population?

CHAT p.Met202Arg (c.605T>G) is rare (popmax 0.105%, afr) (gnomAD).

How is Congenital myasthenic syndrome inherited?

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

What do computational predictors say about CHAT p.Met202Arg (c.605T>G)?

AlphaMissense predicts likely pathogenic (score 0.7382) — an in-silico prediction, not a clinical call.

CHAT p.Met202Arg

c.605T>G · rs376808313 · VCV430062

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7382 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome

Computational evidence

Protein change
AlphaMissense	0.7382	likely pathogenic ✓ concordant with ClinVar
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -11.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	29.5	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 0.105% African / African-American · 79/75,006 alleles

Filtering AF 0.0866% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0797%

Overall 0.00533% 86/1,613,622 alleles · rare exomes 43/1,461,410 · genomes 43/152,212 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.105%	949
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed American	0.00333%	30,008

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.Met202Arg
Coding: c.605T>G
MANE Select: NM_020549
dbSNP: rs376808313
Type: single nucleotide variant
Location: chr10:49620520 (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 202: an α-helix

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

Disease context

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

Also linked: congenital myasthenic syndrome 6

For Congenital myasthenic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CHAT p.Met202Thr Uncertain significance ★ ⚠ same residue
SLC18A3 p.Asp202Gly 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
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-met202arg (accessed [today's date]).

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