Is PRNP p.Trp73Ser (c.218G>C) pathogenic?

PRNP p.Trp73Ser (c.218G>C) is classified Uncertain significance in PRNP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely pathogenic (0.678); Absent from gnomAD v4.1.

How common is PRNP p.Trp73Ser (c.218G>C) in the general population?

PRNP p.Trp73Ser (c.218G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRNP p.Trp73Ser (c.218G>C)?

AlphaMissense predicts likely pathogenic (score 0.678) — an in-silico prediction, not a clinical call.

PRNP p.Trp73Ser

c.218G>C · VCV3336934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.678 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.678	likely pathogenic
REVEL	0.713	pathogenic-leaning
SaProt	LLR -13.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 758 bp · p 0.0025 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Trp73Ser
Coding: c.218G>C
MANE Select: NM_000311
Type: single nucleotide variant
Location: chr20:4699438 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 73: the 'disordered' region; the '5 x 8 aa tandem repeats of p-h-g-g-g-w-g-q' region; a β-strand; the 'interaction with grb2, eri3 and syn1' region

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

Similar variants

PRNP p.Ala117Val Pathogenic ★★ ⚠ same type
PRNP p.Arg148His Likely pathogenic ★★ ⚠ same type
PRNP p.Arg208His Pathogenic/Likely pathogenic ★★ ⚠ same type
PRNP p.Asp178Asn Pathogenic/Likely pathogenic ★★ ⚠ same type
PRNP p.Gln217Arg Likely pathogenic ★★ ⚠ same type
PRNP p.Glu200Lys Pathogenic ★★ ⚠ same type
PRNP p.Gly131Val Pathogenic/Likely pathogenic ★★ same type
PRNP p.Phe198Ser Pathogenic ★★ ⚠ same type

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-trp73ser (accessed [today's date]).

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