Is PRNP p.Pro105Ser (c.313C>T) pathogenic?

PRNP p.Pro105Ser (c.313C>T) is classified Conflicting classifications of pathogenicity in PRNP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-02-06). AlphaMissense: ambiguous (0.4448); Very rare (popmax 8.48e-05%, nfe); Associated with PRNP-related disorder.

What condition is associated with PRNP p.Pro105Ser (c.313C>T)?

PRNP p.Pro105Ser (c.313C>T) is associated with PRNP-related disorder, Gerstmann-Straussler-Scheinker syndrome (ClinVar).

How common is PRNP p.Pro105Ser (c.313C>T) in the general population?

PRNP p.Pro105Ser (c.313C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PRNP p.Pro105Ser (c.313C>T)?

AlphaMissense predicts ambiguous (score 0.4448) — an in-silico prediction, not a clinical call.

PRNP p.Pro105Ser

c.313C>T · rs74315414 · VCV13415

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4448 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

PRNP-related disorder

Computational evidence

Protein change
AlphaMissense	0.4448	ambiguous
REVEL	0.709	pathogenic-leaning
SaProt	LLR -8.97	tolerated
⇒ REVEL calls this damaging; SaProt does not; 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	22.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,926 alleles

Overall 6.2e-05% 1/1,613,938 alleles · very rare exomes 1/1,461,736 · genomes 0/152,202 · joint denominator

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: PRNP
Protein: p.Pro105Ser
Coding: c.313C>T
MANE Select: NM_000311
dbSNP: rs74315414
Type: single nucleotide variant
Location: chr20:4699533 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 105: the 'disordered' region; a UniProt-annotated variant site (in gsd); 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

PRNP-related disorder

Also linked: Gerstmann-Straussler-Scheinker syndrome

Similar variants

PRNP p.Pro105Leu Pathogenic ★ same residue
PRNP p.Pro105Thr Pathogenic 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-pro105ser (accessed [today's date]).

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