Is GLRA1 p.Phe17Ser (c.50T>C) pathogenic?

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.

What condition is associated with GLRA1 p.Phe17Ser (c.50T>C)?

GLRA1 p.Phe17Ser (c.50T>C) is associated with Inborn genetic diseases, hyperekplexia 1, hereditary hyperekplexia (ClinVar).

How common is GLRA1 p.Phe17Ser (c.50T>C) in the general population?

GLRA1 p.Phe17Ser (c.50T>C) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

What do computational predictors say about GLRA1 p.Phe17Ser (c.50T>C)?

AlphaMissense predicts likely benign (score 0.1638) — an in-silico prediction, not a clinical call.

GLRA1 p.Phe17Ser

c.50T>C · rs376426309 · VCV464189

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1638	likely benign
REVEL	0.38	indeterminate
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 96 kb · p 3.9e-15 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0119% European (non-Finnish) · 138/1,156,258 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00967%

Overall 0.00913% 145/1,588,070 alleles · ultra-rare

Ancestry group	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 individualsnot grpmax-eligible	0.00325%	30,800

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GLRA1
Protein: p.Phe17Ser
Coding: c.50T>C
MANE Select: NM_000171
dbSNP: rs376426309
Type: single nucleotide variant
Location: chr5:151924500 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.48 · 9 PDB

Full GLRA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperekplexia 1 hereditary hyperekplexia

Similar variants

GLRA1 p.Phe17Leu Uncertain significance ★★ ⚠ same residue
GLRA1 p.Phe17= Likely benign ★ same residue
GLRA1 c.1059+1G>A Pathogenic/Likely pathogenic ★★ same condition
GLRA1 c.913-1G>A Likely pathogenic ★★ same condition
GLRA1 p.Arg246Trp Pathogenic/Likely pathogenic ★★ same condition
GLRA1 p.Arg280His Pathogenic/Likely pathogenic ★★ same condition
GLRA1 p.Arg299Gln Pathogenic ★★ same condition
GLRA1 p.Arg299Leu Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/glra1-p-phe17ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown