# NM_000171.4(GLRA1):c.50T>C (p.Phe17Ser)

https://sugi.bio/variant/glra1-p-phe17ser

## Summary

**GLRA1 p.Phe17Ser (c.50T>C)** is classified **Conflicting classifications of pathogenicity** in GLRA1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.1638); Ultra-rare (popmax 0.0119%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs376426309 · 4 submitters · 3 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0119%, nfe)

## For patients & families {#patients}

This is a change in the GLRA1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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 | [GLRA1](https://sugi.bio/atlas/gene/GLRA1/) |
| Protein change (HGVS p.) | p.Phe17Ser |
| Coding change (HGVS c.) | c.50T>C |
| MANE Select transcript | [NM_000171](https://www.ncbi.nlm.nih.gov/nuccore/NM_000171) |
| dbSNP | [rs376426309](https://www.ncbi.nlm.nih.gov/snp/rs376426309/) |
| Variant type | single nucleotide variant |
| Location | chr5:151924500-151924500 (GRCh38) |
| ClinVar | [VCV464189](https://www.ncbi.nlm.nih.gov/clinvar/variation/464189/) |

**All HGVS expressions:** `NC_000005.10:g.151924500A>G`, `NC_000005.9:g.151304061A>G`, `NG_011764.1:g.5337T>C`, `NM_000171.4:c.50T>C`, `NM_001146040.2:c.50T>C`, `NM_001292000.2:c.-72T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1638)
- REVEL 0.38 (indeterminate)
- SaProt LLR -7.495 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 11.115, GERP 1.75, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.3**. 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 0.62** across the covering region of the MANE Select transcript (151,828,942–151,924,549), spanning 95,607 bp. Chi-square p 3.9e-15. 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 **0.0119%** (nfe) · FAF95 0.0102% · FAF99 0.00967% · 138/1,156,258 in the highest group · 145/1,588,070 alleles overall — ultra-rare (popmax 0.0119%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0119% | 8,379 |
| African / African-American | 0.00403% | 24,823 |
| Admixed American | 0.00333% | 29,989 |
| Remaining individuals (not grpmax-eligible) | 0.00325% | 30,800 |

*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}

**GLRA1** population constraint: LOEUF 0.975, pLI 1.979e-07, missense-Z 2.4146. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.48, 61% of residues very-high.

**9 experimental structure(s)** (PDB): [1MOT](https://www.rcsb.org/structure/1MOT), [1VRY](https://www.rcsb.org/structure/1VRY), [2M6B](https://www.rcsb.org/structure/2M6B), [2M6I](https://www.rcsb.org/structure/2M6I), [4X5T](https://www.rcsb.org/structure/4X5T), [8DN2](https://www.rcsb.org/structure/8DN2).

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

*Describes the biological roles of GLRA1 (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:** GLRA1's established molecular role includes zinc ion binding.


### Pathways affected {#pathways}

GLRA1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neurotransmitter receptors and postsynaptic signal transmission](https://reactome.org/content/detail/R-HSA-112314) | electronic |

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

**Molecular function:** zinc ion binding, glycine binding, extracellularly glycine-gated chloride channel activity, taurine binding, identical protein binding, ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential.

**Biological process:** startle response, monoatomic ion transport, chloride transport, muscle contraction, neuropeptide signaling pathway, regulation of membrane potential.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-29.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-29 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-16 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [hyperekplexia 1](https://sugi.bio/atlas/disease/hyperekplexia-1/), [hereditary hyperekplexia](https://sugi.bio/atlas/disease/hereditary-hyperekplexia/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Hyperekplexia 1, Hereditary hyperekplexia, STARTLE DISEASE, FAMILIAL, STIFF-BABY SYNDROME, STIFF-MAN SYNDROME, CONGENITAL, STIFF-PERSON SYNDROME, CONGENITAL, HYPEREKPLEXIA 1, AUTOSOMAL DOMINANT, HYPEREKPLEXIA 1, AUTOSOMAL RECESSIVE, EXAGGERATED STARTLE REACTION.

## Similar variants {#similar}

Related GLRA1 variant pages (same residue, condition, or type): [GLRA1 p.Phe17Leu](/variant/glra1-p-phe17leu), [GLRA1 p.Phe17=](/variant/glra1-p-phe17), [GLRA1 c.1059+1G>A](/variant/glra1-c-1059-plus-1g-a), [GLRA1 c.913-1G>A](/variant/glra1-c-913-minus-1g-a), [GLRA1 p.Arg246Trp](/variant/glra1-p-arg246trp), [GLRA1 p.Arg280His](/variant/glra1-p-arg280his), [GLRA1 p.Arg299Gln](/variant/glra1-p-arg299gln), [GLRA1 p.Arg299Leu](/variant/glra1-p-arg299leu).

### 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 2026-10-14); 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 464189). 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.*