Is CHAT p.Trp81Ter (c.243G>A) pathogenic?

CHAT p.Trp81Ter (c.243G>A) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-10-15). Very rare (popmax 0.00196%, amr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Trp81Ter (c.243G>A)?

CHAT p.Trp81Ter (c.243G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Trp81Ter (c.243G>A) in the general population?

CHAT p.Trp81Ter (c.243G>A) is very rare (popmax 0.00196%, amr) (gnomAD).

CHAT p.Trp81Ter

c.243G>A · rs1384661323 · VCV1321379

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 15
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 0.14, phastCons 0.97
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/51,038 alleles

Overall 0.000258% 4/1,547,804 alleles · very rare exomes 4/1,395,488 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00196%	51,038
Remaining individualsnot grpmax-eligible	0.00167%	59,904
African / African-American	0.00137%	73,136
European (non-Finnish)	8.72e-05%	1,146,840

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.Trp81Ter
Coding: c.243G>A
MANE Select: NM_020549
dbSNP: rs1384661323
Type: single nucleotide variant
Location: chr10:49614432 (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 81: the 'disordered' region

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

SLC18A3 p.Thr81Ile 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
CHAT p.Arg207Gly 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-trp81ter (accessed [today's date]).

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