Is CHAT p.Val506Leu (c.1516G>T) pathogenic?

CHAT p.Val506Leu (c.1516G>T) is classified Likely pathogenic in CHAT (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-15). AlphaMissense: likely pathogenic (0.5989); Very rare (popmax 0.00017%, nfe); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Val506Leu (c.1516G>T)?

CHAT p.Val506Leu (c.1516G>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Val506Leu (c.1516G>T) in the general population?

CHAT p.Val506Leu (c.1516G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CHAT p.Val506Leu (c.1516G>T)?

AlphaMissense predicts likely pathogenic (score 0.5989) — an in-silico prediction, not a clinical call.

CHAT p.Val506Leu

c.1516G>T · rs121912817 · VCV17508

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.5989	likely pathogenic ✓ concordant with ClinVar
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.50	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	24.6	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 0.00017% European (non-Finnish) · 2/1,179,782 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,702 alleles · very rare

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.Val506Leu
Coding: c.1516G>T
MANE Select: NM_020549
dbSNP: rs121912817
Type: single nucleotide variant
Location: chr10:49651888 (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 506: a UniProt-annotated variant site (in cms6; impaired activity); 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.Val506= Likely benign ★ same residue
SLC18A3 p.Gly506Ser 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

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-val506leu (accessed [today's date]).

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