Is CHAT p.His252Tyr (c.754C>T) pathogenic?

CHAT p.His252Tyr (c.754C>T) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.12); Rare (popmax 0.203%, eas); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.His252Tyr (c.754C>T)?

CHAT p.His252Tyr (c.754C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.His252Tyr (c.754C>T) in the general population?

CHAT p.His252Tyr (c.754C>T) is rare (popmax 0.203%, eas) (gnomAD).

What do computational predictors say about CHAT p.His252Tyr (c.754C>T)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

CHAT p.His252Tyr

c.754C>T · rs376994468 · VCV707510

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.203%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -9.03	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 3.3	GERP 0.23, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	20.6	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 0.203% East Asian · 91/44,886 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.157%

Overall 0.0102% 164/1,612,314 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.203%	493
Remaining individualsnot grpmax-eligible	0.0481%	2,078
Admixed American	0.0233%	4,287
African / African-American	0.0213%	4,688
South Asian	0.0132%	7,582
European (non-Finnish)	8.47e-05%	1,179,967

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.His252Tyr
Coding: c.754C>T
MANE Select: NM_020549
dbSNP: rs376994468
Type: single nucleotide variant
Location: chr10:49625474 (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

SLC18A3 p.Ser252Leu 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-his252tyr (accessed [today's date]).

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