Is CHAT p.Leu249Val (c.745C>G) pathogenic?

CHAT p.Leu249Val (c.745C>G) is classified Benign/Likely benign in CHAT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1269); Low-frequency (popmax 1.25%, afr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Leu249Val (c.745C>G)?

CHAT p.Leu249Val (c.745C>G) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Leu249Val (c.745C>G) in the general population?

CHAT p.Leu249Val (c.745C>G) is low-frequency (popmax 1.25%, afr) (gnomAD).

What do computational predictors say about CHAT p.Leu249Val (c.745C>G)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

CHAT p.Leu249Val

c.745C>G · rs115510708 · VCV210707

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.25%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.18, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	19.45	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 1.25% African / African-American · 851/68,136 alleles

Filtering AF 1.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.15%

Overall 0.0628% 976/1,553,504 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.25%	80
Middle Eastern	0.122%	821
Admixed American	0.0836%	1,196
Remaining individualsnot grpmax-eligible	0.0743%	1,347
South Asian	0.00556%	17,990
European (non-Finnish)	0.00192%	52,115

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.Leu249Val
Coding: c.745C>G
MANE Select: NM_020549
dbSNP: rs115510708
Type: single nucleotide variant
Location: chr10:49622143 (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 249: 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.Leu249= Likely benign ★ same residue
CHAT p.Leu249fs Pathogenic ★ 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-leu249val (accessed [today's date]).

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