GJA8 p.Arg76Pro
c.227G>C · VCV4909127
Likely pathogenic
Single submitter
Classification
Likely pathogenic
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely pathogenic
0.9868 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
3/3 damaging
AlphaMissense, REVEL, SaProt
Conditions
1
GJA8-related disorders
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9868 | likely pathogenic ✓ concordant with ClinVar · top 6% in GJA8 |
|---|---|---|
| REVEL | 0.993 | strongly pathogenic-leaning |
| SaProt | LLR -14.27 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 9.8 | GERP 2.4, phastCons 1 |
| Regional constraint | o/e 1.10 | unconstrained · MANE · 1,298 bp · p 0.022 · regional, not allelic |
| Overall | ||
| CADD | 30.0 | 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
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- GJA8
- Protein
- p.Arg76Pro
- Coding
- c.227G>C
- MANE Select
- NM_005267
- Type
- single nucleotide variant
- Location
- chr1:147908182 (GRCh38)
- Gene constraint
- LOEUF 1.304 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 65.85
- Residue 76
- a UniProt-annotated variant site (in ctrct1)
Disease context
GJA8-related disorders
Similar variants
- GJA8 p.Arg76Ser Uncertain significance ★ ⚠ same residue
- GJA8 p.Arg76His Likely pathogenic ★★ same residue
- GJA8 p.Arg76Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
- GJA8 p.Arg76Gly Uncertain significance ★ ⚠ same residue
- GJA8 p.Gly22Arg Likely pathogenic ★★ same condition
- GJA8 p.Pro88Leu Pathogenic/Likely pathogenic ★★ same condition
- GJA8 p.Ser258Phe Pathogenic/Likely pathogenic ★★ ⚠ same condition
- GJA8 p.Trp45Ser 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/gja8-p-arg76pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown