Is PRNP p.Gln75= (c.225G>A) pathogenic?

PRNP p.Gln75= (c.225G>A) is classified Likely benign in PRNP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-09). Ultra-rare (popmax 0.0169%, mid); Associated with Huntington disease-like 1.

What condition is associated with PRNP p.Gln75= (c.225G>A)?

PRNP p.Gln75= (c.225G>A) is associated with Huntington disease-like 1 (ClinVar).

How common is PRNP p.Gln75= (c.225G>A) in the general population?

PRNP p.Gln75= (c.225G>A) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

How is Huntington disease-like 1 inherited?

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

PRNP p.Gln75=

c.225G>A · rs776922173 · VCV1607151

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

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 -0.67	GERP -0.49, phastCons 0.001
Overall
CADD	0.605	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Middle Eastern · 1/5,930 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00192% 31/1,610,866 alleles · ultra-rare exomes 27/1,459,288 · genomes 4/151,578 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,930
Remaining individualsnot grpmax-eligible	0.00642%	15,572
Admixed American	0.00334%	29,923
European (non-Finnish)	0.00195%	51,242
African / African-American	0.00134%	74,384

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.Gln75=
Coding: c.225G>A
MANE Select: NM_000311
dbSNP: rs776922173
Type: single nucleotide variant
Location: chr20:4699445 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 75: the 'disordered' region; the '5 x 8 aa tandem repeats of p-h-g-g-g-w-g-q' region; a turn; 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-gln75 (accessed [today's date]).

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