# NM_000156.6(GAMT):c.228A>T (p.Ser76=)

https://sugi.bio/variant/gamt-p-ser76

## Summary

**GAMT p.Ser76= (c.228A>T)** is classified **Uncertain significance** in GAMT (ClinVar, Expert panel, 3 submitters; last evaluated 2024-10-08). Ultra-rare (popmax 0.0101%, amr); Associated with guanidinoacetate methyltransferase deficiency.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs752364729 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0101%, amr)

## For patients & families {#patients}

This is a change in the GAMT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to guanidinoacetate methyltransferase deficiency.

*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 recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GAMT is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Guanidinoacetate methyltransferase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Seizure — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Abnormality of extrapyramidal motor function — Frequent (79-30%)
- Poor speech — Frequent (79-30%)
- Progressive extrapyramidal movement disorder — Frequent (79-30%)
- Intellectual disability, severe — Frequent (79-30%)
- Severe global developmental delay — Frequent (79-30%)
- Abnormality of movement — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002578/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GAMT](https://sugi.bio/atlas/gene/GAMT/) |
| Protein change (HGVS p.) | p.Ser76= |
| Coding change (HGVS c.) | c.228A>T |
| MANE Select transcript | [NM_000156](https://www.ncbi.nlm.nih.gov/nuccore/NM_000156) |
| dbSNP | [rs752364729](https://www.ncbi.nlm.nih.gov/snp/rs752364729/) |
| Variant type | single nucleotide variant |
| Location | chr19:1399892-1399892 (GRCh38) |
| ClinVar | [VCV1552732](https://www.ncbi.nlm.nih.gov/clinvar/variation/1552732/) |

**All HGVS expressions:** `NC_000019.10:g.1399892T>A`, `NC_000019.9:g.1399891T>A`, `NG_009785.1:g.6662A>T`, `NM_000156.6:c.228A>T`, `NM_138924.3:c.228A>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 -2.061, GERP -3.11 — fast-evolving / accelerated position
- CADD: **PHRED 0.566**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GAMT (266 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0101%** (amr) · FAF95 0.00431% · FAF99 0.00297% · 6/59,514 in the highest group · 8/1,608,564 alleles overall — ultra-rare (popmax 0.0101%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0101% | 9,919 |
| European (non-Finnish) | 0.00017% | 589,202 |

*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}

**GAMT** population constraint: LOEUF 1.536, pLI 2.6125e-10, missense-Z -2.3611; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **guanidinoacetate methyltransferase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **76** lies in the rmt2 domain; a UniProt-annotated variant site (no effect on enzymatic activity); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.73, 97% of residues very-high.

**1 experimental structure(s)** (PDB): [3ORH](https://www.rcsb.org/structure/3ORH).

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

*Describes the biological roles of GAMT (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:** GAMT's established molecular role includes guanidinoacetate N-methyltransferase activity. p.Ser76= falls in the rmt2 domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Creatine metabolism](https://reactome.org/content/detail/R-HSA-71288) | curated |
| [Transcriptional Regulation by MECP2](https://reactome.org/content/detail/R-HSA-8986944) | electronic |

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

**Molecular function:** guanidinoacetate N-methyltransferase activity.

**Biological process:** creatine biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-10-08.

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

**Submission history:** 3 submissions (2020–2024); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — Cerebral Creatine Deficiency Syndromes VCEP (guanidinoacetate methyltransferase deficiency). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `BP7`, `BP4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000156.6:c.228A>T (p.Ser76=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -0.250) (BP4, BP7). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001008 (6/59514 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1552732). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50047 · approved 2024-10-08 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/c0b25d34-300f-4066-a90f-4e5bf4bf85c0).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| AiLife Diagnostics, AiLife Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-05-05 |
| ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Uncertain significance | reviewed by expert panel | curation | 2024-10-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-06 |

## Associated conditions {#conditions}

[guanidinoacetate methyltransferase deficiency](https://sugi.bio/atlas/disease/guanidinoacetate-methyltransferase-deficiency/), [cerebral creatine deficiency syndrome](https://sugi.bio/atlas/disease/cerebral-creatine-deficiency-syndrome/).

**Reported phenotype names (ClinVar):** Deficiency of guanidinoacetate methyltransferase, Cerebral creatine deficiency syndrome, not provided, GAMT DEFICIENCY, Guanidinoacetate Methyltransferase (GAMT) Deficiency, CEREBRAL CREATINE DEFICIENCY SYNDROME 2, Creatine deficiency syndromes, none provided.

## Similar variants {#similar}

Related GAMT variant pages (same residue, condition, or type): [GAMT p.Ser76Leu](/variant/gamt-p-ser76leu), [GAMT p.Ser76Pro](/variant/gamt-p-ser76pro), [GAMT c.327+43G>A](/variant/gamt-c-327-plus-43g-a), [GAMT c.328-1G>A](/variant/gamt-c-328-minus-1g-a), [GAMT c.328-2A>G](/variant/gamt-c-328-minus-2a-g), [GAMT c.391+15G>T](/variant/gamt-c-391-plus-15g-t), [GAMT c.391+1G>C](/variant/gamt-c-391-plus-1g-c), [GAMT c.391+5G>C](/variant/gamt-c-391-plus-5g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1552732). 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.*