Is CHAT p.Pro552Ser (c.1654C>T) pathogenic?

CHAT p.Pro552Ser (c.1654C>T) is classified Benign in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1613); Rare (popmax 0.162%, amr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Pro552Ser (c.1654C>T)?

CHAT p.Pro552Ser (c.1654C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Pro552Ser (c.1654C>T) in the general population?

CHAT p.Pro552Ser (c.1654C>T) is rare (popmax 0.162%, amr) (gnomAD).

What do computational predictors say about CHAT p.Pro552Ser (c.1654C>T)?

AlphaMissense predicts likely benign (score 0.1613) — an in-silico prediction, not a clinical call.

CHAT p.Pro552Ser

c.1654C>T · rs147079245 · VCV461451

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1613 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.162%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.1613	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP 1, phastCons 0.035
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	18.25	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 0.162% Admixed American · 97/60,024 alleles

Filtering AF 0.136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.126%

Overall 0.0112% 181/1,614,118 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.162%	619
Remaining individualsnot grpmax-eligible	0.0176%	5,682
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0061%	16,389

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.Pro552Ser
Coding: c.1654C>T
MANE Select: NM_020549
dbSNP: rs147079245
Type: single nucleotide variant
Location: chr10:49655114 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.73 · 8 PDB

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.Pro552= 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
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-pro552ser (accessed [today's date]).

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