Is PRG4 p.Phe103Ser (c.308T>C) pathogenic?

PRG4 p.Phe103Ser (c.308T>C) is classified Uncertain significance in PRG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-16). AlphaMissense: ambiguous (0.5339); Very rare (popmax 0.00333%, amr); Associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

What condition is associated with PRG4 p.Phe103Ser (c.308T>C)?

PRG4 p.Phe103Ser (c.308T>C) is associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (ClinVar).

How common is PRG4 p.Phe103Ser (c.308T>C) in the general population?

PRG4 p.Phe103Ser (c.308T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PRG4 p.Phe103Ser (c.308T>C)?

AlphaMissense predicts ambiguous (score 0.5339) — an in-silico prediction, not a clinical call.

PRG4 p.Phe103Ser

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.308T>C · rs768957112 · VCV2435241

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5339 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

camptodactyly-arthropathy-coxa vara-pericarditis syndrome

Computational evidence

Protein change
AlphaMissense	0.5339	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -3.06	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 10 kb · p 0.3 · regional, not allelic
Overall
CADD	24.1	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

Grpmax group 0.00333% Admixed American · 2/59,996 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,613,764 alleles · very rare exomes 2/1,461,616 · genomes 1/152,148 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,998
European (non-Finnish)	8.48e-05%	1,179,805

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.Phe103Ser
Coding: c.308T>C
MANE Select: NM_005807
dbSNP: rs768957112
Type: single nucleotide variant
Location: chr1:186301700 (GRCh38)
Gene constraint: LOEUF 0.801 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.76
Residue 103: the smb 2 domain

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

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PRG4 p.Arg180Trp Benign/Likely benign ★★ ⚠ same condition
PRG4 p.Pro1046= 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-phe103ser (accessed [today's date]).

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