Is PRG4 p.Pro378Ser (c.1132C>T) pathogenic?

PRG4 p.Pro378Ser (c.1132C>T) is classified Uncertain significance in PRG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-07). AlphaMissense: likely benign (0.1089); Very rare (popmax 0.00145%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PRG4 p.Pro378Ser (c.1132C>T)?

PRG4 p.Pro378Ser (c.1132C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRG4 p.Pro378Ser (c.1132C>T) in the general population?

PRG4 p.Pro378Ser (c.1132C>T) is very rare (popmax 0.00145%, nfe) (gnomAD).

What do computational predictors say about PRG4 p.Pro378Ser (c.1132C>T)?

AlphaMissense predicts likely benign (score 0.1089) — an in-silico prediction, not a clinical call.

PRG4 p.Pro378Ser

c.1132C>T · rs1417592943 · VCV2558322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1089 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00145%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1089	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -1.8
Regional constraint	o/e 0.95	unconstrained · MANE · 10 kb · p 0.3 · regional, not allelic
Overall
CADD	0.102	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00145% European (non-Finnish) · 17/1,176,096 alleles

Filtering AF 0.000881% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00072%

Overall 0.0015% 24/1,602,122 alleles · very rare exomes 23/1,460,866 · genomes 1/141,256 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00796%	12,565
Remaining individualsnot grpmax-eligible	0.00321%	31,136
European (non-Finnish)grpmax	0.00145%	69,182

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: PRG4
Protein: p.Pro378Ser
Coding: c.1132C>T
MANE Select: NM_005807
dbSNP: rs1417592943
Type: single nucleotide variant
Location: chr1:186306851 (GRCh38)
Gene constraint: LOEUF 0.801 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.76
Residue 378: the 'disordered' region; the '59 x 8 aa repeats of k-x-p-x-p-t-t-x' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRG4 p.Ala1246Val Uncertain significance ★★ ⚠ same condition
PRG4 p.Asp87Asn Uncertain significance ★★ ⚠ same condition
PRG4 p.Lys287Arg Uncertain significance ★★ ⚠ same condition
PRG4 p.Pro409Leu Uncertain significance ★★ ⚠ same condition
PRG4 p.Val1399Phe Uncertain significance ★★ ⚠ same condition
PRG4 p.Ala641Thr Likely benign ★★ same condition
PRG4 p.Glu403Lys Likely benign ★★ same condition
PRG4 p.Leu648= Likely benign ★★ 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-pro378ser (accessed [today's date]).

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