Is GJC2 p.Pro331= (c.993C>G) pathogenic?

GJC2 p.Pro331= (c.993C>G) is classified Likely benign in GJC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). Ultra-rare (popmax 0.0217%, nfe); Associated with Spastic paraplegia.

What condition is associated with GJC2 p.Pro331= (c.993C>G)?

GJC2 p.Pro331= (c.993C>G) is associated with Spastic paraplegia (ClinVar).

How common is GJC2 p.Pro331= (c.993C>G) in the general population?

GJC2 p.Pro331= (c.993C>G) is ultra-rare (popmax 0.0217%, nfe) (gnomAD).

GJC2 p.Pro331=

c.993C>G · rs891962078 · VCV1121305

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, nfe)

Conditions

Spastic paraplegia

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 -20
Overall
CADD	0.104	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% European (non-Finnish) · 232/1,066,892 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0185%

Overall 0.019% 263/1,383,026 alleles · ultra-rare exomes 233/1,234,000 · genomes 30/149,026 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0509%	1,964
European (non-Finnish)grpmax	0.0217%	4,599
Remaining individualsnot grpmax-eligible	0.0157%	6,354
African / African-American	0.0031%	32,212
Admixed American	0.00292%	34,216

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GJC2
Protein: p.Pro331=
Coding: c.993C>G
MANE Select: NM_020435
dbSNP: rs891962078
Type: single nucleotide variant
Location: chr1:228158751 (GRCh38)
Gene constraint: LOEUF 1.604 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 68.50

Full GJC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GJC2 p.Ala123Ser Uncertain significance ★★ ⚠ same condition
GJC2 p.Ala177Val Uncertain significance ★★ ⚠ same condition
GJC2 p.Ala221Pro Uncertain significance ★★ ⚠ same condition
GJC2 p.Ala340Val Uncertain significance ★★ ⚠ same condition
GJC2 p.Arg115Cys Uncertain significance ★★ ⚠ same condition
GJC2 p.Arg11Gln Uncertain significance ★★ ⚠ same condition
GJC2 p.Arg203His Uncertain significance ★★ ⚠ same condition
GJC2 p.Arg247Cys 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/gjc2-p-pro331 (accessed [today's date]).

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