Is PRNP p.Pro102Ser (c.304C>T) pathogenic?

PRNP p.Pro102Ser (c.304C>T) is classified Likely pathogenic in PRNP (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: ambiguous (0.4861); Absent from gnomAD v4.1; Associated with Gerstmann-Straussler-Scheinker syndrome.

What condition is associated with PRNP p.Pro102Ser (c.304C>T)?

PRNP p.Pro102Ser (c.304C>T) is associated with Gerstmann-Straussler-Scheinker syndrome (ClinVar).

How common is PRNP p.Pro102Ser (c.304C>T) in the general population?

PRNP p.Pro102Ser (c.304C>T) is absent from gnomAD v4.1 (gnomAD).

How is Gerstmann-Straussler-Scheinker syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRNP p.Pro102Ser (c.304C>T)?

AlphaMissense predicts ambiguous (score 0.4861) — an in-silico prediction, not a clinical call.

PRNP p.Pro102Ser

c.304C>T · VCV3366860

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4861 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Gerstmann-Straussler-Scheinker syndrome

Computational evidence

Protein change
AlphaMissense	0.4861	ambiguous
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -11.06	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 758 bp · p 0.0025 · regional, not allelic
Overall
CADD	24.0	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: PRNP
Protein: p.Pro102Ser
Coding: c.304C>T
MANE Select: NM_000311
Type: single nucleotide variant
Location: chr20:4699524 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 102: the 'disordered' region; a UniProt-annotated variant site (in gsd and early-onset dementia); an α-helix; the 'interaction with grb2, eri3 and syn1' region

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

Disease context

Gerstmann-Straussler-Scheinker syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Gerstmann-Straussler-Scheinker syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult

Similar variants

PRNP p.Pro102Leu Pathogenic ★★ same residue
PRNP p.Pro102= Benign/Likely benign ★★ same residue
PRNP p.Ala117Val Pathogenic ★★ ⚠ same condition
PRNP p.Asp178Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRNP p.Gln217Arg Likely pathogenic ★★ ⚠ same condition
PRNP p.Glu200Lys Pathogenic ★★ ⚠ same condition
PRNP p.Gly131Val Pathogenic/Likely pathogenic ★★ same condition
PRNP p.Phe198Ser 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/prnp-p-pro102ser (accessed [today's date]).

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