Is CHAT p.Thr462Met (c.1385C>T) pathogenic?

CHAT p.Thr462Met (c.1385C>T) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-07-18). AlphaMissense: likely benign (0.0697); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with CHAT p.Thr462Met (c.1385C>T)?

CHAT p.Thr462Met (c.1385C>T) is associated with Inborn genetic diseases, congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Thr462Met (c.1385C>T) in the general population?

CHAT p.Thr462Met (c.1385C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CHAT p.Thr462Met (c.1385C>T)?

AlphaMissense predicts likely benign (score 0.0697) — an in-silico prediction, not a clinical call.

CHAT p.Thr462Met

c.1385C>T · rs538478136 · VCV642070

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0697 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0697	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -8.16	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 0.2	GERP -2.1, phastCons 0.045
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	11.03	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00793% 128/1,613,792 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.209%	477
Middle Easterngrpmax	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0208%	4,808
South Asian	0.0187%	5,357
Admixed American	0.0183%	5,457
European (non-Finnish)	0.00186%	53,639
Finnishnot grpmax-eligible	0.00157%	63,620

Ashkenazi Jewish 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.Thr462Met
Coding: c.1385C>T
MANE Select: NM_020549
dbSNP: rs538478136
Type: single nucleotide variant
Location: chr10:49649510 (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 462: an α-helix

Full CHAT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 6

Similar variants

CHAT p.Thr462= 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-thr462met (accessed [today's date]).

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