Is CHAT p.Ser240Phe (c.719C>T) pathogenic?

CHAT p.Ser240Phe (c.719C>T) is classified Uncertain significance in CHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-29). AlphaMissense: ambiguous (0.4128); Very rare (popmax 0.00635%, afr); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Ser240Phe (c.719C>T)?

CHAT p.Ser240Phe (c.719C>T) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Ser240Phe (c.719C>T) in the general population?

CHAT p.Ser240Phe (c.719C>T) is very rare (popmax 0.00635%, afr) (gnomAD).

What do computational predictors say about CHAT p.Ser240Phe (c.719C>T)?

AlphaMissense predicts ambiguous (score 0.4128) — an in-silico prediction, not a clinical call.

CHAT p.Ser240Phe

c.719C>T · rs1269023544 · VCV863804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00635%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.4128	ambiguous
REVEL	0.71	pathogenic-leaning
SaProt	LLR -10.53	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	25.9	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 0.00635% African / African-American · 3/47,208 alleles

Filtering AF 0.00169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000867%

Overall 0.000443% 6/1,355,092 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00635%	15,736
Remaining individualsnot grpmax-eligible	0.00203%	49,360
European (non-Finnish)	0.000193%	518,148

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.Ser240Phe
Coding: c.719C>T
MANE Select: NM_020549
dbSNP: rs1269023544
Type: single nucleotide variant
Location: chr10:49622117 (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 240: 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

SLC18A3 p.Gly240Arg 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-ser240phe (accessed [today's date]).

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