# NM_000481.4(AMT):c.100C>T (p.Arg34Cys)

https://sugi.bio/variant/amt-p-arg34cys

## Summary

**AMT p.Arg34Cys (c.100C>T)** is classified **Uncertain significance** in AMT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-05). AlphaMissense: likely benign (0.1375); Very rare (popmax 0.00534%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs143389339 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00534%, nfe)

## For patients & families {#patients}

This is a change in the AMT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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 | [AMT](https://sugi.bio/atlas/gene/AMT/) |
| Protein change (HGVS p.) | p.Arg34Cys |
| Coding change (HGVS c.) | c.100C>T |
| MANE Select transcript | [NM_000481](https://www.ncbi.nlm.nih.gov/nuccore/NM_000481) |
| dbSNP | [rs143389339](https://www.ncbi.nlm.nih.gov/snp/rs143389339/) |
| Variant type | single nucleotide variant |
| Location | chr3:49422262-49422262 (GRCh38) |
| ClinVar | [VCV581326](https://www.ncbi.nlm.nih.gov/clinvar/variation/581326/) |

**All HGVS expressions:** `LRG_537:g.5417C>T`, `LRG_537t1:c.100C>T`, `NC_000003.11:g.49459695G>A`, `NC_000003.12:g.49422262G>A`, `NG_015986.1:g.5417C>T`, `NG_033046.1:g.12063C>T`, `NM_000481.4:c.100C>T`, `NM_001164710.2:c.100C>T`, `NM_001164711.2:c.90+99C>T`, `NM_001164712.2:c.100C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1375)
- REVEL 0.468 (indeterminate)
- SaProt LLR -9.763 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 4.549, GERP 1.11, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.6**. 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 0.93** across the covering region of the MANE Select transcript (49,417,543–49,422,450), spanning 4,907 bp. Chi-square p 0.12. 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 (G>T, Δ0.39 acceptor loss), 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 **0.00534%** (nfe) · FAF95 0.00426% · FAF99 0.00387% · 63/1,179,994 in the highest group · 71/1,613,882 alleles overall — very rare (popmax 0.00534%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,927 |
| European (non-Finnish) (grpmax) | 0.00534% | 18,730 |
| Admixed American | 0.00167% | 60,002 |

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}

**AMT** population constraint: LOEUF 0.805, pLI 0.00010023, missense-Z 1.0014. *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):

- **glycine encephalopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.66, 91% of residues very-high.

**2 experimental structure(s)** (PDB): [1WSR](https://www.rcsb.org/structure/1WSR), [1WSV](https://www.rcsb.org/structure/1WSV).

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

*Describes the biological roles of AMT (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:** AMT's established molecular role includes aminomethyltransferase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycine degradation](https://reactome.org/content/detail/R-HSA-6783984) | curated |

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

**Molecular function:** aminomethyltransferase activity.

**Biological process:** glycine decarboxylation via glycine cleavage system.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-07-05.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2019–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2019-10-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-05 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-19 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [glycine encephalopathy](https://sugi.bio/atlas/disease/glycine-encephalopathy/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Glycine encephalopathy, Non-ketotic hyperglycinemia, Nonketotic hyperglycinemia.

## Similar variants {#similar}

Related AMT variant pages (same residue, condition, or type): [AMT p.Arg34His](/variant/amt-p-arg34his), [AMT p.Arg34=](/variant/amt-p-arg34), [AMT c.339+2T>C](/variant/amt-c-339-plus-2t-c), [AMT c.471+2T>C](/variant/amt-c-471-plus-2t-c), [AMT c.697-1G>A](/variant/amt-c-697-minus-1g-a), [AMT c.878-1G>A](/variant/amt-c-878-minus-1g-a), [AMT c.91-2A>G](/variant/amt-c-91-minus-2a-g), [AMT c.-58C>T](/variant/amt-c-minus-58c-t).

### 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 581326). 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.*