Is CHAT p.Val306Ile (c.916G>A) pathogenic?

CHAT p.Val306Ile (c.916G>A) is classified Conflicting classifications of pathogenicity in CHAT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1471); Rare (popmax 0.124%, sas); Associated with congenital myasthenic syndrome 6.

What condition is associated with CHAT p.Val306Ile (c.916G>A)?

CHAT p.Val306Ile (c.916G>A) is associated with congenital myasthenic syndrome 6 (ClinVar).

How common is CHAT p.Val306Ile (c.916G>A) in the general population?

CHAT p.Val306Ile (c.916G>A) is rare (popmax 0.124%, sas) (gnomAD).

What do computational predictors say about CHAT p.Val306Ile (c.916G>A)?

AlphaMissense predicts likely benign (score 0.1471) — an in-silico prediction, not a clinical call.

CHAT p.Val306Ile

c.916G>A · rs551219437 · VCV1166325

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1471 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.124%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 6

Computational evidence

Protein change
AlphaMissense	0.1471	likely benign
REVEL	0.584	indeterminate
SaProt	LLR -8.78	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 9.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 32 kb · p 0.16 · regional, not allelic
Overall
CADD	25.0	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 0.124% South Asian · 107/86,238 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0979%

Overall 0.00819% 129/1,574,434 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.124%	806
Remaining individualsnot grpmax-eligible	0.00819%	12,211
Admixed American	0.00371%	26,943
African / African-American	0.00269%	37,114
European (non-Finnish)	0.00112%	89,142

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.Val306Ile
Coding: c.916G>A
MANE Select: NM_020549
dbSNP: rs551219437
Type: single nucleotide variant
Location: chr10:49625636 (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 306: a β-strand

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.Val306Ala Likely pathogenic ★ same residue
CHAT p.Val306Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SLC18A3 p.Ala306Ser 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

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-val306ile (accessed [today's date]).

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