Is PRNP p.Met232Arg (c.695T>G) pathogenic?

PRNP p.Met232Arg (c.695T>G) is classified Uncertain significance in PRNP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-11-01). AlphaMissense: likely benign (0.1393); Rare (popmax 0.408%, eas); Associated with kuru, susceptibility to.

What condition is associated with PRNP p.Met232Arg (c.695T>G)?

PRNP p.Met232Arg (c.695T>G) is associated with kuru, susceptibility to, inherited Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (ClinVar).

How common is PRNP p.Met232Arg (c.695T>G) in the general population?

PRNP p.Met232Arg (c.695T>G) is rare (popmax 0.408%, eas) (gnomAD).

What do computational predictors say about PRNP p.Met232Arg (c.695T>G)?

AlphaMissense predicts likely benign (score 0.1393) — an in-silico prediction, not a clinical call.

PRNP p.Met232Arg

c.695T>G · rs74315409 · VCV13406

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1393 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.408%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

kuru, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.1393	likely benign
REVEL	0.587	indeterminate
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.049	GERP -2.6
Regional constraint	o/e 0.84	unconstrained · MANE · 758 bp · p 0.0025 · regional, not allelic
Overall
CADD	13.9	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 0.408% East Asian · 183/44,866 alleles

Filtering AF 0.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.341%

Overall 0.0115% 185/1,613,938 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.408%	245
Remaining individualsnot grpmax-eligible	0.0032%	31,251

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.Met232Arg
Coding: c.695T>G
MANE Select: NM_000311
dbSNP: rs74315409
Type: single nucleotide variant
Location: chr20:4699915 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 232: a UniProt-annotated variant site (in cjd)

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

Disease context

kuru, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited Creutzfeldt-Jakob disease Gerstmann-Straussler-Scheinker syndrome fatal familial insomnia Huntington disease-like 1 spongiform encephalopathy with neuropsychiatric features

Similar variants

PRNP p.Met232Ile Uncertain significance ★ ⚠ same residue
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

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-met232arg (accessed [today's date]).

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