# NM_020549.5(CHAT):c.903T>C (p.Pro301=)

https://sugi.bio/variant/chat-p-pro301

## Summary

**CHAT p.Pro301= (c.903T>C)** is classified **Benign** in CHAT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with congenital myasthenic syndrome 6.

**At a glance:** Benign · review: Multiple submitters · rsID rs113897064 · 5 submitters · 1 linked condition · common (popmax 5%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CHAT gene that is classified as benign — not considered disease-causing, submitted by 5 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.Pro301= |
| Coding change (HGVS c.) | c.903T>C |
| MANE Select transcript | [NM_020549](https://www.ncbi.nlm.nih.gov/nuccore/NM_020549) |
| dbSNP | [rs113897064](https://www.ncbi.nlm.nih.gov/snp/rs113897064/) |
| Variant type | single nucleotide variant |
| Location | chr10:49625623-49625623 (GRCh38) |
| ClinVar | [VCV128727](https://www.ncbi.nlm.nih.gov/clinvar/variation/128727/) |

**All HGVS expressions:** `NC_000010.10:g.50833669T>C`, `NC_000010.11:g.49625623T>C`, `NG_011797.1:g.21529T>C`, `NM_001142929.2:c.549T>C`, `NM_001142933.2:c.657T>C`, `NM_001142934.2:c.549T>C`, `NM_020549.5:c.903T>C`, `NM_020984.4:c.549T>C`, `NM_020985.4:c.549T>C`, `NM_020986.4:c.549T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5%, afr) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -12.054, GERP -4.65 — fast-evolving / accelerated position
- CADD: **PHRED 0.04**. 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.*
- 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 **5%** (afr) · FAF95 4.87% · FAF99 4.81% · 3,732/74,596 in the highest group · 4,260/1,589,482 alleles overall — common (popmax 5%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 5% | 20 |
| Remaining individuals (not grpmax-eligible) | 0.372% | 269 |
| Admixed American | 0.368% | 272 |
| Middle Eastern | 0.199% | 503 |
| South Asian | 0.016% | 6,264 |
| European (non-Finnish) | 0.00565% | 17,684 |

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (4 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing | 2017-09-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-08-30 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## 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, not provided, AllHighlyPenetrant, none provided, MYASTHENIC SYNDROME, CONGENITAL, 6, PRESYNAPTIC, Congenital myasthenic syndrome type 6, MYASTHENIC SYNDROME, PRESYNAPTIC, CONGENITAL, ASSOCIATED WITH EPISODIC APNEA.

## Similar variants {#similar}

Related CHAT variant pages (same residue, condition, or type): [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), [CHAT p.Arg207His](/variant/chat-p-arg207his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 128727). 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.*