Is PRNP p.Pro68= (c.204T>C) pathogenic?

PRNP p.Pro68= (c.204T>C) is classified Benign/Likely benign in PRNP (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-11-06). Rare (popmax 0.566%, afr); Associated with Huntington disease-like 1.

What condition is associated with PRNP p.Pro68= (c.204T>C)?

PRNP p.Pro68= (c.204T>C) is associated with Huntington disease-like 1 (ClinVar).

How common is PRNP p.Pro68= (c.204T>C) in the general population?

PRNP p.Pro68= (c.204T>C) is rare (popmax 0.566%, afr) (gnomAD).

How is Huntington disease-like 1 inherited?

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

PRNP p.Pro68=

c.204T>C · rs532493114 · VCV338647

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.566%, afr)

Conditions

Huntington disease-like 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -2.9
Overall
CADD	0.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.566% African / African-American · 418/73,896 alleles

Filtering AF 0.521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.503%

Overall 0.1% 1,609/1,606,432 alleles · rare exomes 1,233/1,455,866 · genomes 376/150,566 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.566%	177
East Asian	0.392%	255
Middle Eastern	0.173%	577
Remaining individualsnot grpmax-eligible	0.138%	722
Admixed American	0.106%	944
European (non-Finnish)	0.0697%	1,435
South Asian	0.0355%	2,816
Ashkenazi Jewishnot grpmax-eligible	0.017%	5,897

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.Pro68=
Coding: c.204T>C
MANE Select: NM_000311
dbSNP: rs532493114
Type: single nucleotide variant
Location: chr20:4699424 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 68: the 'disordered' region; the '5 x 8 aa tandem repeats of p-h-g-g-g-w-g-q' region; the 'interaction with grb2, eri3 and syn1' region

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

For Huntington disease-like 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

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.Phe198Ser 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-pro68 (accessed [today's date]).

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