# NM_020549.5(CHAT):c.406G>A (p.Val136Met)

https://sugi.bio/variant/chat-p-val136met

## Summary

**CHAT p.Val136Met (c.406G>A)** is classified **Conflicting classifications of pathogenicity** in CHAT (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-03-19). AlphaMissense: ambiguous (0.5351); Very rare (popmax 0.00915%, nfe); Associated with congenital myasthenic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201479289 · 9 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00915%, nfe)

## For patients & families {#patients}

This is a change in the CHAT gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to congenital myasthenic syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 13 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CHAT is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Congenital myasthenic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neck muscle weakness — Very frequent (99-80%)
- Ptosis — Very frequent (99-80%)
- Dysphagia — Very frequent (99-80%)
- Poor suck — Very frequent (99-80%)
- Sudden episodic apnea — Very frequent (99-80%)
- Fatigable weakness — Very frequent (99-80%)
- Proximal muscle weakness — Very frequent (99-80%)
- Frontalis muscle weakness — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0011902/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHAT](https://sugi.bio/atlas/gene/CHAT/) |
| Protein change (HGVS p.) | p.Val136Met |
| Coding change (HGVS c.) | c.406G>A |
| MANE Select transcript | [NM_020549](https://www.ncbi.nlm.nih.gov/nuccore/NM_020549) |
| dbSNP | [rs201479289](https://www.ncbi.nlm.nih.gov/snp/rs201479289/) |
| Variant type | single nucleotide variant |
| Location | chr10:49619743-49619743 (GRCh38) |
| ClinVar | [VCV279754](https://www.ncbi.nlm.nih.gov/clinvar/variation/279754/) |

**All HGVS expressions:** `NC_000010.10:g.50827789G>A`, `NC_000010.11:g.49619743G>A`, `NG_011797.1:g.15649G>A`, `NM_001142929.2:c.52G>A`, `NM_001142933.2:c.160G>A`, `NM_001142934.2:c.52G>A`, `NM_020549.5:c.406G>A`, `NM_020984.4:c.52G>A`, `NM_020985.4:c.52G>A`, `NM_020986.4:c.52G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5351) — no call either way
- REVEL 0.804 (moderately pathogenic-leaning)
- SaProt LLR -10.525 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 11.788, GERP 2.05, phastCons 1 — highly conserved
- CADD: **PHRED 26.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.06** across the covering region of the MANE Select transcript (49,614,190–49,646,558), spanning 32,368 bp. Chi-square p 0.16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00915%** (nfe) · FAF95 0.00774% · FAF99 0.00719% · 108/1,179,984 in the highest group · 129/1,612,480 alleles overall — very rare (popmax 0.00915%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,240 |
| European (non-Finnish) (grpmax) | 0.00915% | 10,926 |
| African / African-American | 0.00801% | 12,480 |
| Admixed American | 0.00667% | 14,998 |
| South Asian | 0.0011% | 91,028 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CHAT** population constraint: LOEUF 0.973, pLI 9.9145e-17, missense-Z 0.67235; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **congenital myasthenic syndrome 6** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.73, 75% of residues very-high.

**8 experimental structure(s)** (PDB): [2FY2](https://www.rcsb.org/structure/2FY2), [2FY3](https://www.rcsb.org/structure/2FY3), [2FY4](https://www.rcsb.org/structure/2FY4), [2FY5](https://www.rcsb.org/structure/2FY5), [7AMD](https://www.rcsb.org/structure/7AMD), [9F84](https://www.rcsb.org/structure/9F84).

## What this gene does {#gene-function}

*Describes the biological roles of CHAT (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

CHAT participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [Acetylcholine Neurotransmitter Release Cycle](https://reactome.org/content/detail/R-HSA-264642) | other |

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-03-19.

**Submitter consensus:** conflicting (6 Pathogenic, 2 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 9 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-05-10 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-01-24 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-20 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-05 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-12-21 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-21 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-07-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-31 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2026-03-19 |

## Associated conditions {#conditions}

[congenital myasthenic syndrome](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome/), [congenital myasthenic syndrome 6](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-6/).

**Reported phenotype names (ClinVar):** Congenital myasthenic syndrome, not provided, Familial infantile myasthenia, Congenital Myasthenic Syndromes, none provided, MYASTHENIC SYNDROME, PRESYNAPTIC, CONGENITAL, ASSOCIATED WITH EPISODIC APNEA, MYASTHENIC SYNDROME, CONGENITAL, 6, PRESYNAPTIC, Congenital myasthenic syndrome type 6.

## Similar variants {#similar}

Related CHAT variant pages (same residue, condition, or type): [SLC18A3 p.Leu136=](/variant/slc18a3-p-leu136), [CHAT c.1282-2A>T](/variant/chat-c-1282-minus-2a-t), [CHAT c.1840-9A>G](/variant/chat-c-1840-minus-9a-g), [CHAT c.698+1G>T](/variant/chat-c-698-plus-1g-t), [CHAT c.698+2T>C](/variant/chat-c-698-plus-2t-c), [CHAT p.Ala557Thr](/variant/chat-p-ala557thr), [CHAT p.Arg151Ter](/variant/chat-p-arg151ter), [CHAT p.Arg207Gly](/variant/chat-p-arg207gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 279754). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*