Is GJA8 p.Ser73Pro (c.217T>C) pathogenic?

GJA8 p.Ser73Pro (c.217T>C) is classified Likely pathogenic in GJA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-21). AlphaMissense: likely pathogenic (0.984); Absent from gnomAD v4.1; Associated with cataract 1 multiple types.

What condition is associated with GJA8 p.Ser73Pro (c.217T>C)?

GJA8 p.Ser73Pro (c.217T>C) is associated with cataract 1 multiple types (ClinVar).

How common is GJA8 p.Ser73Pro (c.217T>C) in the general population?

GJA8 p.Ser73Pro (c.217T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GJA8 p.Ser73Pro (c.217T>C)?

AlphaMissense predicts likely pathogenic (score 0.984) — an in-silico prediction, not a clinical call.

GJA8 p.Ser73Pro

c.217T>C · rs2524889508 · VCV3253724

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 1 multiple types

Computational evidence

Protein change
AlphaMissense	0.984	likely pathogenic ✓ concordant with ClinVar · top 7% in GJA8
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -13.68	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 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,298 bp · p 0.022 · regional, not allelic
Overall
CADD	25.3	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

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.Ser73Pro
Coding: c.217T>C
MANE Select: NM_005267
dbSNP: rs2524889508
Type: single nucleotide variant
Location: chr1:147908172 (GRCh38)
Gene constraint: LOEUF 1.304 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 65.85
Residue 73: a UniProt-annotated variant site (in ctrct1)

Full GJA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 1 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GJA8 p.Ser73Phe Likely pathogenic ★ same residue
GJA8 p.Arg76His Likely pathogenic ★★ same condition
GJA8 p.Asp47His Pathogenic/Likely pathogenic ★★ same condition
GJA8 p.Gly22Arg Likely pathogenic ★★ same condition
GJA8 p.Gly22Ser Pathogenic/Likely pathogenic ★★ same condition
GJA8 p.Gly46Glu Pathogenic ★★ same condition
GJA8 p.Gly60Ser Pathogenic/Likely pathogenic ★★ same condition
GJA8 p.Pro88Ala 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-ser73pro (accessed [today's date]).

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