Is PRNP p.Val189Ile (c.565G>A) pathogenic?

PRNP p.Val189Ile (c.565G>A) is classified Uncertain significance in PRNP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-12). AlphaMissense: likely benign (0.1172); Very rare (popmax 0.00267%, afr); Associated with Inherited prion disease.

What condition is associated with PRNP p.Val189Ile (c.565G>A)?

PRNP p.Val189Ile (c.565G>A) is associated with Inherited prion disease (ClinVar).

How common is PRNP p.Val189Ile (c.565G>A) in the general population?

PRNP p.Val189Ile (c.565G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PRNP p.Val189Ile (c.565G>A)?

AlphaMissense predicts likely benign (score 0.1172) — an in-silico prediction, not a clinical call.

PRNP p.Val189Ile

c.565G>A · rs1178466848 · VCV896504

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inherited prion disease

Computational evidence

Protein change
AlphaMissense	0.1172	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -5.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.61, phastCons 0.98
Regional constraint	o/e 0.84	unconstrained · MANE · 758 bp · p 0.0025 · regional, not allelic
Overall
CADD	10.97	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 0.00267% African / African-American · 2/74,854 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,613,884 alleles · very rare exomes 4/1,461,880 · genomes 4/152,004 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,427
European (non-Finnish)	0.000508%	196,671

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.Val189Ile
Coding: c.565G>A
MANE Select: NM_000311
dbSNP: rs1178466848
Type: single nucleotide variant
Location: chr20:4699785 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 189: 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

Inherited prion disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRNP c.*206A>G Benign ★★ same condition
PRNP c.*4A>T Benign ★★ same condition
PRNP c.*682A>G Benign ★★ same condition
PRNP c.*697A>G Benign ★★ same condition
PRNP c.*70G>A Benign/Likely benign ★★ same condition
PRNP p.Ala117= Benign/Likely benign ★★ same condition
PRNP p.Asn171Ser Benign ★★ same condition
PRNP p.Glu219Lys Benign ★★ 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-val189ile (accessed [today's date]).

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