Is PRG4 p.Pro1046= (c.3138A>G) pathogenic?

PRG4 p.Pro1046= (c.3138A>G) is classified Benign/Likely benign in PRG4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-26). Common (popmax 41.1%, amr) — too common for a highly-penetrant pathogenic allele; Associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

What condition is associated with PRG4 p.Pro1046= (c.3138A>G)?

PRG4 p.Pro1046= (c.3138A>G) is associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (ClinVar).

PRG4 p.Pro1046=

Q: How common is PRG4 p.Pro1046= (c.3138A>G) in the general population?

PRG4 p.Pro1046= (c.3138A>G) is common (popmax 41.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Camptodactyly-arthropathy-coxa-vara-pericarditis syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.3138A>G · rs3737940 · VCV518311

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 41.1%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

camptodactyly-arthropathy-coxa vara-pericarditis syndrome

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 -1.1	GERP -2.5
Overall
CADD	2.277	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 41.1% Admixed American · 24,672/59,994 alleles

Filtering AF 40.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.5%

Overall 32% 516,554/1,613,490 alleles · common exomes 474,471/1,461,400 · genomes 42,083/152,090 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	41.1%	2
Ashkenazi Jewishnot grpmax-eligible	35.1%	3
European (non-Finnish)	34.3%	3
Middle Eastern	31.8%	3
Remaining individualsnot grpmax-eligible	30.5%	3
Finnishnot grpmax-eligible	28.9%	3
South Asian	23.1%	4
African / African-American	14.3%	7
Amishnot grpmax-eligible	12.6%	8
East Asian	11.8%	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: PRG4
Protein: p.Pro1046=
Coding: c.3138A>G
MANE Select: NM_005807
dbSNP: rs3737940
Type: single nucleotide variant
Location: chr1:186308857 (GRCh38)
Gene constraint: LOEUF 0.801 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.76
Residue 1046: the 'disordered' region

Full PRG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

camptodactyly-arthropathy-coxa vara-pericarditis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Camptodactyly-arthropathy-coxa-vara-pericarditis syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

PRG4 p.Pro1046Ala Uncertain significance ★ ⚠ same residue
PRG4 p.Arg1166Ter Pathogenic/Likely pathogenic ★★ same condition
PRG4 p.Ser1355Ter Pathogenic/Likely pathogenic ★★ same condition
PRG4 c.-30-30T>A Benign ★★ same condition
PRG4 p.Arg180Trp Benign/Likely benign ★★ ⚠ same condition
PRG4 p.Thr604Ala Benign/Likely benign ★★ ⚠ same condition
PRG4 p.Glu101Ter Pathogenic ★ same condition
PRG4 p.Leu321Ter 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/prg4-p-pro1046 (accessed [today's date]).

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