# NM_001171038.2(ASMT):c.366C>T (p.Asp122=)

https://sugi.bio/variant/asmt-p-asp122

## Summary

**ASMT p.Asp122= (c.366C>T)** is classified **Likely benign** in ASMT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-03-30). Ultra-rare (popmax 0.0933%, afr); Associated with ASMT-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs151095769 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0933%, afr)

## For patients & families {#patients}

This is a change in the ASMT gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to ASMT-related disorder.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ASMT](https://sugi.bio/atlas/gene/ASMT/) |
| Protein change (HGVS p.) | p.Asp122= |
| Coding change (HGVS c.) | c.366C>T |
| MANE Select transcript | [NM_001171038](https://www.ncbi.nlm.nih.gov/nuccore/NM_001171038) |
| dbSNP | [rs151095769](https://www.ncbi.nlm.nih.gov/snp/rs151095769/) |
| Variant type | single nucleotide variant |
| Location | chrX:1624390-1624390 (GRCh38) |
| ClinVar | [VCV3029851](https://www.ncbi.nlm.nih.gov/clinvar/variation/3029851/) |

**All HGVS expressions:** `NC_000023.10:g.1743283C>T`, `NC_000023.11:g.1624390C>T`, `NC_000024.10:g.1624390C>T`, `NC_000024.9:g.1693283C>T`, `NG_016337.1:g.33936C>T`, `NM_001171038.2:c.366C>T`, `NM_001171039.1:c.366C>T`, `NM_001416525.1:c.366C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -0.645, GERP -3.6 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.329**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.24 donor 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 **0.0933%** (afr) · FAF95 0.0757% · FAF99 0.0693% · 70/74,988 in the highest group · 241/1,613,262 alleles overall — ultra-rare (popmax 0.0933%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0933% | 1,071 |
| Middle Eastern | 0.0535% | 1,871 |
| Remaining individuals (not grpmax-eligible) | 0.0224% | 4,460 |
| Admixed American | 0.0133% | 7,500 |
| European (non-Finnish) | 0.0117% | 8,549 |
| East Asian | 0.00669% | 14,957 |
| South Asian | 0.00549% | 18,207 |

*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.*

## Protein context {#protein}

Residue **122** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 95.55, 94% of residues very-high.

**2 experimental structure(s)** (PDB): [4A6D](https://www.rcsb.org/structure/4A6D), [4A6E](https://www.rcsb.org/structure/4A6E).

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

*Describes the biological roles of ASMT (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.*

**How this variant is thought to act:** ASMT's established molecular role includes acetylserotonin O-methyltransferase activity.


### Pathways affected {#pathways}

ASMT participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Serotonin and melatonin biosynthesis](https://reactome.org/content/detail/R-HSA-209931) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** acetylserotonin O-methyltransferase activity, identical protein binding, protein homodimerization activity.

**Biological process:** melatonin biosynthetic process.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2021-03-30.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-03-30 |

## Associated conditions {#conditions}

[ASMT-related disorder](https://sugi.bio/atlas/disease/asmt-related-disorder/).

**Reported phenotype names (ClinVar):** ASMT-related disorder, ASMT-related condition.

## Similar variants {#similar}

Related ASMT variant pages (same residue, condition, or type): [ASMT p.Arg210=](/variant/asmt-p-arg210), [ASMT p.Asp287=](/variant/asmt-p-asp287), [ASMT p.Trp190Arg](/variant/asmt-p-trp190arg), [ASMT c.910+8del](/variant/asmt-c-910-plus-8del), [ASMT p.Lys81Glu](/variant/asmt-p-lys81glu), [ASMT c.562+2T>C](/variant/asmt-c-562-plus-2t-c), [ASMT p.Asn17Lys](/variant/asmt-p-asn17lys), [ASMT p.Cys29Ter](/variant/asmt-p-cys29ter).

### 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 3029851). 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.*