Is CHAT p.Leu243Phe (c.727C>T) pathogenic?

CHAT p.Leu243Phe (c.727C>T) is classified Benign/Likely benign in CHAT (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: ambiguous (0.3815); Common (popmax 6.45%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Leu243Phe (c.727C>T)?

CHAT p.Leu243Phe (c.727C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

What do computational predictors say about CHAT p.Leu243Phe (c.727C>T)?

AlphaMissense predicts ambiguous (score 0.3815) — an in-silico prediction, not a clinical call.

CHAT p.Leu243Phe

Q: How common is CHAT p.Leu243Phe (c.727C>T) in the general population?

CHAT p.Leu243Phe (c.727C>T) is common (popmax 6.45%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.727C>T · rs8178990 · VCV128726

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.3815 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.45%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.3815	ambiguous
REVEL	0.733	pathogenic-leaning
SaProt	LLR -10.67	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	25.9	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 6.45% European (non-Finnish) · 75,964/1,177,744 alleles

Filtering AF 6.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.4%

Overall 5.66% 91,165/1,610,118 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	10.8%	9
Amishnot grpmax-eligible	9.6%	10
European (non-Finnish)grpmax	6.45%	16
Ashkenazi Jewishnot grpmax-eligible	5.56%	18
Remaining individualsnot grpmax-eligible	5.24%	19
Admixed American	2.35%	43
Middle Eastern	1.67%	60
South Asian	1.27%	79
African / African-American	0.913%	110
East Asian	0.00446%	22,414

Finnish 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.Leu243Phe
Coding: c.727C>T
MANE Select: NM_020549
dbSNP: rs8178990
Type: single nucleotide variant
Location: chr10:49622125 (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 243: a UniProt-annotated variant site (in); 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

SLC18A3 p.Val243Leu 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-leu243phe (accessed [today's date]).

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