Is PRNP p.Arg136Ser (c.408G>T) pathogenic?

PRNP p.Arg136Ser (c.408G>T) is classified Uncertain significance in PRNP (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.9134); Ultra-rare (popmax 0.055%, amr); Associated with Huntington disease-like 1.

What condition is associated with PRNP p.Arg136Ser (c.408G>T)?

PRNP p.Arg136Ser (c.408G>T) is associated with Huntington disease-like 1 (ClinVar).

How common is PRNP p.Arg136Ser (c.408G>T) in the general population?

PRNP p.Arg136Ser (c.408G>T) is ultra-rare (popmax 0.055%, amr) (gnomAD).

How is Huntington disease-like 1 inherited?

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

What do computational predictors say about PRNP p.Arg136Ser (c.408G>T)?

AlphaMissense predicts likely pathogenic (score 0.9134) — an in-silico prediction, not a clinical call.

PRNP p.Arg136Ser

c.408G>T · rs146315846 · VCV1503725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9134 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Huntington disease-like 1

Computational evidence

Protein change
AlphaMissense	0.9134	likely pathogenic
REVEL	0.635	indeterminate
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.51, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 758 bp · p 0.0025 · regional, not allelic
Overall
CADD	18.16	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.055% Admixed American · 33/59,988 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.00217% 35/1,613,982 alleles · ultra-rare exomes 12/1,461,862 · genomes 23/152,120 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.055%	1,818
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	8.47e-05%	1,180,008

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.Arg136Ser
Coding: c.408G>T
MANE Select: NM_000311
dbSNP: rs146315846
Type: single nucleotide variant
Location: chr20:4699628 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.18 · 70 PDB
Residue 136: an α-helix; 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.Arg136Thr Uncertain significance ★ ⚠ same residue
PRNP p.Arg136= Likely benign ★ same residue
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-arg136ser (accessed [today's date]).

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