# NM_004961.4(GABRE):c.304T>G (p.Ser102Ala)

https://sugi.bio/variant/gabre-p-ser102ala

## Summary

**GABRE p.Ser102Ala (c.304T>G)** is classified **Benign** in GABRE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-09-14). AlphaMissense: likely benign (0.0821); Common (popmax 89.1%, eas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs1139916 · 2 submitters · AlphaMissense likely benign · common (popmax 89.1%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the GABRE gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [GABRE](https://sugi.bio/atlas/gene/GABRE/) |
| Protein change (HGVS p.) | p.Ser102Ala |
| Coding change (HGVS c.) | c.304T>G |
| MANE Select transcript | [NM_004961](https://www.ncbi.nlm.nih.gov/nuccore/NM_004961) |
| dbSNP | [rs1139916](https://www.ncbi.nlm.nih.gov/snp/rs1139916/) |
| Variant type | single nucleotide variant |
| Location | chrX:151969707-151969707 (GRCh38) |
| ClinVar | [VCV1280403](https://www.ncbi.nlm.nih.gov/clinvar/variation/1280403/) |

**All HGVS expressions:** `NC_000023.10:g.151138179A>C`, `NC_000023.11:g.151969707A>C`, `NG_012511.1:g.9973T>G`, `NM_004961.4:c.304T>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 89.1%, eas) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0821)
- REVEL 0.211 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.2 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.285, GERP 3.37, phastCons 0.989 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 13.69**. 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 1.02** across the covering region of the MANE Select transcript (151,954,704–151,974,625), spanning 19,921 bp. Chi-square p 0.65. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **89.1%** (eas) · FAF95 88.2% · FAF99 87.9% · 29,946/33,612 in the highest group · 833,708/1,206,120 alleles overall — common (popmax 89.1%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 89.1% | 1 |
| South Asian | 81.7% | 1 |
| Finnish (not grpmax-eligible) | 79.7% | 1 |
| Admixed American | 73.3% | 1 |
| Middle Eastern | 70.6% | 1 |
| European (non-Finnish) | 68.3% | 1 |
| Remaining individuals (not grpmax-eligible) | 68.3% | 1 |
| Amish (not grpmax-eligible) | 62.3% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 61% | 2 |
| African / African-American | 49.2% | 2 |

*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 **102** lies in a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 73.13, 40% of residues very-high.

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

*Describes the biological roles of GABRE (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:** GABRE's established molecular role includes GABA-A receptor activity.


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

**Molecular function:** GABA-A receptor activity, GABA-gated chloride ion channel activity.

**Biological process:** negative regulation of chloride transport.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2020-09-14.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2020); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-09-14 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Pharmacogenomics (PharmGKB) {#pgx}

Drugs with reported response associations: botulinum toxin type a.
*PharmGKB levels 1A/1B (highest) → 4. Discuss any medication decision with your prescriber — reference information, not advice.*

## Similar variants {#similar}

Related GABRE variant pages (same residue, condition, or type): [GABRE p.Arg176His](/variant/gabre-p-arg176his), [GABRE p.Asn134=](/variant/gabre-p-asn134), [GABRE p.Glu435Asp](/variant/gabre-p-glu435asp), [GABRE p.Gly62=](/variant/gabre-p-gly62), [GABRE p.Leu323=](/variant/gabre-p-leu323), [GABRE p.Ala193Gly](/variant/gabre-p-ala193gly), [GABRE p.Ala193Thr](/variant/gabre-p-ala193thr), [GABRE p.Ala193Val](/variant/gabre-p-ala193val).

### 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 1280403). 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.*