# NM_020549.5(CHAT):c.619C>T (p.Arg207Cys)

https://sugi.bio/variant/chat-p-arg207cys

## Summary

**CHAT p.Arg207Cys (c.619C>T)** is classified **Conflicting classifications of pathogenicity** in CHAT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-30). AlphaMissense: ambiguous (0.4734); Very rare (popmax 0.00329%, sas); Associated with congenital myasthenic syndrome 6.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs760936252 · 3 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00329%, sas)

## 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 3 submitters, and is linked to congenital myasthenic syndrome 6.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009689/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.Arg207Cys |
| Coding change (HGVS c.) | c.619C>T |
| MANE Select transcript | [NM_020549](https://www.ncbi.nlm.nih.gov/nuccore/NM_020549) |
| dbSNP | [rs760936252](https://www.ncbi.nlm.nih.gov/snp/rs760936252/) |
| Variant type | single nucleotide variant |
| Location | chr10:49620534-49620534 (GRCh38) |
| ClinVar | [VCV577871](https://www.ncbi.nlm.nih.gov/clinvar/variation/577871/) |

**All HGVS expressions:** `NC_000010.10:g.50828580C>T`, `NC_000010.11:g.49620534C>T`, `NG_011797.1:g.16440C>T`, `NM_001142929.2:c.265C>T`, `NM_001142933.2:c.373C>T`, `NM_001142934.2:c.265C>T`, `NM_020549.5:c.619C>T`, `NM_020984.4:c.265C>T`, `NM_020985.4:c.265C>T`, `NM_020986.4:c.265C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.4734) — no call either way
- REVEL 0.888 (moderately pathogenic-leaning)
- SaProt LLR -12.086 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 7.647, GERP 2.38, phastCons 1 — highly conserved
- CADD: **PHRED 29.9**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.50 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00329%** (sas) · FAF95 0.000875% · FAF99 0.000443% · 3/91,078 in the highest group · 12/1,613,772 alleles overall — very rare (popmax 0.00329%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00329% | 30,359 |
| East Asian | 0.00223% | 44,856 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,466 |
| European (non-Finnish) | 0.000593% | 168,554 |

*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 gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 2025-07-30.

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

**Submission history:** 3 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-08 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-30 |
| Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Likely pathogenic | criteria provided, single submitter | research |  |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial infantile myasthenia, not specified, AllHighlyPenetrant, MYASTHENIC SYNDROME, CONGENITAL, 6, PRESYNAPTIC, Congenital myasthenic syndrome type 6, MYASTHENIC SYNDROME, PRESYNAPTIC, CONGENITAL, ASSOCIATED WITH EPISODIC APNEA.

## Same-residue context {#hotspot}

Residue **207** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [CHAT p.Arg207fs](/variant/chat-p-arg207fs), [CHAT p.Arg207His](/variant/chat-p-arg207his), [CHAT p.Arg207Gly](/variant/chat-p-arg207gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CHAT variant pages (same residue, condition, or type): [CHAT p.Arg207Gly](/variant/chat-p-arg207gly), [CHAT p.Arg207His](/variant/chat-p-arg207his), [CHAT p.Arg207=](/variant/chat-p-arg207), [CHAT p.Arg207fs](/variant/chat-p-arg207fs), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 577871). 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.*