# NM_020686.6(ABAT):c.68C>A (p.Pro23His)

https://sugi.bio/variant/abat-p-pro23his

## Summary

**ABAT p.Pro23His (c.68C>A)** is classified **Uncertain significance** in ABAT (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-18). AlphaMissense: likely benign (0.0844); No allele count reported in gnomAD v4.1 (AN 1,602,330); Associated with GABA aminotransaminase deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs369376388 · 1 submitter · 1 linked condition · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,602,330)

## For patients & families {#patients}

This is a change in the ABAT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to GABA aminotransaminase 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) | Infancy, Neonatal |
| Diagnostic panels | ABAT is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Gamma-aminobutyric acid transaminase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Epileptic encephalopathy — Obligate (100%)
- Hypotonia — Very frequent (99-80%)
- EEG abnormality — Very frequent (99-80%)
- Cerebral dysmyelination — Very frequent (99-80%)
- Severe global developmental delay — Very frequent (99-80%)
- Elevated CSF gamma-aminobutyric acid concentration — Very frequent (99-80%)
- Elevated circulating gamma-aminobutyric acid concentration — Very frequent (99-80%)
- Increased level of gamma-aminobutyric acid in urine — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000194/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABAT](https://sugi.bio/atlas/gene/ABAT/) |
| Protein change (HGVS p.) | p.Pro23His |
| Coding change (HGVS c.) | c.68C>A |
| MANE Select transcript | [NM_020686](https://www.ncbi.nlm.nih.gov/nuccore/NM_020686) |
| dbSNP | [rs369376388](https://www.ncbi.nlm.nih.gov/snp/rs369376388/) |
| Variant type | single nucleotide variant |
| Location | chr16:8735807-8735807 (GRCh38) |
| ClinVar | [VCV1010607](https://www.ncbi.nlm.nih.gov/clinvar/variation/1010607/) |

**All HGVS expressions:** `NC_000016.10:g.8735807C>A`, `NC_000016.9:g.8829664C>A`, `NG_008432.1:g.66221C>A`, `NM_000663.5:c.68C>A`, `NM_001127448.2:c.68C>A`, `NM_001386600.1:c.68C>A`, `NM_001386601.1:c.68C>A`, `NM_001386602.1:c.68C>A`, `NM_001386603.1:c.68C>A`, `NM_001386604.1:c.68C>A`, `NM_001386605.1:c.68C>A`, `NM_001386606.1:c.68C>A`, `NM_001386607.1:c.68C>A`, `NM_001386608.1:c.68C>A`, `NM_001386609.1:c.68C>A`, `NM_001386610.1:c.68C>A`, `NM_001386611.1:c.-65-10194C>A`, `NM_001386612.1:c.-65-10194C>A`, `NM_001386613.1:c.-65-10194C>A`, `NM_001386614.1:c.68C>A`, `NM_001386615.1:c.68C>A`, `NM_001386616.1:c.68C>A`, `NM_020686.6:c.68C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0844)
- REVEL 0.254 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.441 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.657, GERP -0.623, phastCons 0.002 — weakly conserved position
- CADD: **PHRED 16.47**. 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 0.96** across the covering region of the MANE Select transcript (8,735,740–8,781,427), spanning 45,687 bp. Chi-square p 0.32. 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>G, Δ0.64 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: **no allele count reported in gnomAD v4.1 (AN 1,602,330)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ABAT** population constraint: LOEUF 0.871, pLI 1.1757e-10, missense-Z 0.75346; 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):

- **genetic developmental and epileptic encephalopathy** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.91, 92% of residues very-high.

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

*Describes the biological roles of ABAT (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:** ABAT's established molecular role includes pyridoxal phosphate binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of GABA](https://reactome.org/content/detail/R-HSA-916853) | curated |

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

**Molecular function:** pyridoxal phosphate binding, 4-aminobutyrate:2-oxoglutarate transaminase activity, identical protein binding.

**Biological process:** obsolete GABA metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-02-18.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-02-18 |

## Associated conditions {#conditions}

[GABA aminotransaminase deficiency](https://sugi.bio/atlas/disease/gaba-aminotransaminase-deficiency/).

**Reported phenotype names (ClinVar):** Gamma-aminobutyric acid transaminase deficiency, GABA transaminase deficiency, Gamma aminobutyrate transaminase deficiency, 4 alpha aminobutyrate transaminase deficiency, GABA aminotransaminase deficiency.

## Similar variants {#similar}

Related ABAT variant pages (same residue, condition, or type): [ABAT c.168+1G>A](/variant/abat-c-168-plus-1g-a), [ABAT p.Arg92Gln](/variant/abat-p-arg92gln), [ABAT p.Gln8Ter](/variant/abat-p-gln8ter), [ABAT p.Leu211Phe](/variant/abat-p-leu211phe), [ABAT p.Tyr376Ter](/variant/abat-p-tyr376ter), [ABAT c.1381+6G>T](/variant/abat-c-1381-plus-6g-t), [ABAT p.Ala162Thr](/variant/abat-p-ala162thr), [ABAT p.Ala226Val](/variant/abat-p-ala226val).

### 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 1010607). 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.*