Is GABBR2 p.Pro684= (c.2052C>T) pathogenic?

GABBR2 p.Pro684= (c.2052C>T) is classified Benign in GABBR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 26.4%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Epileptic encephalopathy.

GABBR2 p.Pro684=

Q: What condition is associated with GABBR2 p.Pro684= (c.2052C>T)?

GABBR2 p.Pro684= (c.2052C>T) is associated with Epileptic encephalopathy, developmental and epileptic encephalopathy, 59, neurodevelopmental disorder with poor language and loss of hand skills (ClinVar).

Q: How common is GABBR2 p.Pro684= (c.2052C>T) in the general population?

GABBR2 p.Pro684= (c.2052C>T) is common (popmax 26.4%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2052C>T · rs2304389 · VCV1167956

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 26.4%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

Epileptic encephalopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.2	GERP -3.6
Overall
CADD	1.252	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 26.4% Middle Eastern · 1,602/6,060 alleles

Filtering AF 25.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.9%

Overall 16.5% 265,434/1,613,292 alleles · common exomes 240,257/1,461,090 · genomes 25,177/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	26.4%	4
South Asian	21.2%	5
Admixed American	19.2%	5
Amishnot grpmax-eligible	18.8%	5
East Asian	17.4%	6
Remaining individualsnot grpmax-eligible	17.1%	6
African / African-American	17%	6
European (non-Finnish)	16%	6
Finnishnot grpmax-eligible	13.4%	7
Ashkenazi Jewishnot grpmax-eligible	13%	8

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: GABBR2
Protein: p.Pro684=
Coding: c.2052C>T
MANE Select: NM_005458
dbSNP: rs2304389
Type: single nucleotide variant
Location: chr9:98306298 (GRCh38)
Gene constraint: LOEUF 0.394 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.00 · 26 PDB
Residue 684: a turn

Full GABBR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Epileptic encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 59 neurodevelopmental disorder with poor language and loss of hand skills

Similar variants

GABBR2 p.Ala567Thr Pathogenic ★★ same condition
GABBR2 p.Ala707Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
GABBR2 p.Gly693Trp Pathogenic ★★ same condition
GABBR2 p.Met702Val Likely pathogenic ★★ same condition
GABBR2 p.Ser695Asn Pathogenic/Likely pathogenic ★★ same condition
GABBR2 c.1662+1G>A Uncertain significance ★★ same condition
GABBR2 p.Ala444Thr Uncertain significance ★★ ⚠ same condition
GABBR2 p.Ala580Ser Uncertain significance ★★ ⚠ 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/gabbr2-p-pro684 (accessed [today's date]).

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