Is CHAT p.Pro299Leu (c.896C>T) pathogenic?

CHAT p.Pro299Leu (c.896C>T) is classified Benign/Likely benign in CHAT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.3183); Low-frequency (popmax 1.37%, afr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Pro299Leu (c.896C>T)?

CHAT p.Pro299Leu (c.896C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Pro299Leu (c.896C>T) in the general population?

CHAT p.Pro299Leu (c.896C>T) is low-frequency (popmax 1.37%, afr) (gnomAD).

What do computational predictors say about CHAT p.Pro299Leu (c.896C>T)?

AlphaMissense predicts likely benign (score 0.3183) — an in-silico prediction, not a clinical call.

CHAT p.Pro299Leu

c.896C>T · rs868749 · VCV261339

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3183 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.37%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.3183	likely benign
REVEL	0.575	indeterminate
SaProt	LLR -5.46	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 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	26.5	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 1.37% African / African-American · 1,025/74,682 alleles

Filtering AF 1.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.27%

Overall 0.0705% 1,125/1,595,084 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.37%	73
Remaining individualsnot grpmax-eligible	0.0647%	1,545
Admixed American	0.0559%	1,788
Middle Eastern	0.0331%	3,018
South Asian	0.0034%	29,411
East Asian	0.00226%	44,206
European (non-Finnish)	0.00188%	53,188

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.Pro299Leu
Coding: c.896C>T
MANE Select: NM_020549
dbSNP: rs868749
Type: single nucleotide variant
Location: chr10:49625616 (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 299: a UniProt-annotated variant site (in)

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.Pro299Ser Uncertain significance ★ same residue
CHAT p.Pro299= Likely benign ★ 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-pro299leu (accessed [today's date]).

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