Is CHAT p.Tyr146= (c.438C>T) pathogenic?

CHAT p.Tyr146= (c.438C>T) is classified Benign/Likely benign in CHAT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Rare (popmax 0.371%, nfe); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Tyr146= (c.438C>T)?

CHAT p.Tyr146= (c.438C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Tyr146= (c.438C>T) in the general population?

CHAT p.Tyr146= (c.438C>T) is rare (popmax 0.371%, nfe) (gnomAD).

CHAT p.Tyr146=

c.438C>T · rs61731734 · VCV261336

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.371%, nfe)

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.21	GERP 1, phastCons 0.25
Overall
CADD	5.282	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.371% European (non-Finnish) · 4,372/1,180,024 alleles

Filtering AF 0.361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.358%

Overall 0.329% 5,303/1,614,028 alleles · rare exomes 4,991/1,461,688 · genomes 312/152,340 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.4%	72
Remaining individualsnot grpmax-eligible	0.437%	229
European (non-Finnish)grpmax	0.371%	270
Admixed American	0.138%	723
Finnishnot grpmax-eligible	0.123%	810
Middle Eastern	0.117%	853
African / African-American	0.056%	1,787
South Asian	0.0362%	2,760
East Asian	0.00223%	44,882

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: CHAT
Protein: p.Tyr146=
Coding: c.438C>T
MANE Select: NM_020549
dbSNP: rs61731734
Type: single nucleotide variant
Location: chr10:49619775 (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 146: 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 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
CHAT p.Arg207Gly Likely pathogenic ★★ same condition
CHAT p.Arg207His 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-tyr146 (accessed [today's date]).

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