Is PRNP p.Phe198Ser (c.593T>C) pathogenic?

PRNP p.Phe198Ser (c.593T>C) is classified Pathogenic in PRNP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.971); Absent from gnomAD v4.1; Associated with Huntington disease-like 1.

What condition is associated with PRNP p.Phe198Ser (c.593T>C)?

PRNP p.Phe198Ser (c.593T>C) is associated with Huntington disease-like 1, Gerstmann-Straussler-Scheinker syndrome (ClinVar).

How common is PRNP p.Phe198Ser (c.593T>C) in the general population?

PRNP p.Phe198Ser (c.593T>C) is absent from gnomAD v4.1 (gnomAD).

How is Huntington disease-like 1 inherited?

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

What do computational predictors say about PRNP p.Phe198Ser (c.593T>C)?

AlphaMissense predicts likely pathogenic (score 0.971) — an in-silico prediction, not a clinical call.

PRNP p.Phe198Ser

c.593T>C · rs74315405 · VCV13401

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.971 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Huntington disease-like 1

Computational evidence

Protein change
AlphaMissense	0.971	likely pathogenic ✓ concordant with ClinVar · top 8% in PRNP
REVEL	0.666	pathogenic-leaning
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 758 bp · p 0.0025 · regional, not allelic
Overall
CADD	22.5	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.Phe198Ser
Coding: c.593T>C
MANE Select: NM_000311
dbSNP: rs74315405
Type: single nucleotide variant
Location: chr20:4699813 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 198: a disulfide bond; a UniProt-annotated variant site (in gsd; atypical form with neurofibrillary tangles); the 'interaction with grb2, eri3 and syn1' region; a β-strand

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

Disease context

Huntington disease-like 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Gerstmann-Straussler-Scheinker syndrome

For Huntington disease-like 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PRNP p.Ala117Val Pathogenic ★★ ⚠ same condition
PRNP p.Arg148His Likely pathogenic ★★ ⚠ same condition
PRNP p.Arg208His Pathogenic/Likely 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.Pro102Leu 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-phe198ser (accessed [today's date]).

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