Is PRDM8 p.Pro574Arg (c.1721C>G) pathogenic?

PRDM8 p.Pro574Arg (c.1721C>G) is classified Uncertain significance in PRDM8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-20). AlphaMissense: likely pathogenic (0.8747); Ultra-rare (popmax 0.0135%, nfe); Associated with early-onset Lafora body disease.

What condition is associated with PRDM8 p.Pro574Arg (c.1721C>G)?

PRDM8 p.Pro574Arg (c.1721C>G) is associated with early-onset Lafora body disease (ClinVar).

How common is PRDM8 p.Pro574Arg (c.1721C>G) in the general population?

PRDM8 p.Pro574Arg (c.1721C>G) is ultra-rare (popmax 0.0135%, nfe) (gnomAD).

How is PRDM8-related progressive myoclonus epilepsy inherited?

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

What do computational predictors say about PRDM8 p.Pro574Arg (c.1721C>G)?

AlphaMissense predicts likely pathogenic (score 0.8747) — an in-silico prediction, not a clinical call.

PRDM8 p.Pro574Arg

c.1721C>G · rs746174564 · VCV648808

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8747 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

early-onset Lafora body disease

Computational evidence

Protein change
AlphaMissense	0.8747	likely pathogenic
REVEL	0.34	indeterminate
SaProt	LLR -11.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,448 bp · p 0.16 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0135% European (non-Finnish) · 155/1,151,646 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.011%

Overall 0.0105% 163/1,549,940 alleles · ultra-rare exomes 159/1,397,912 · genomes 4/152,028 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0135%	7,430
Remaining individualsnot grpmax-eligible	0.00997%	10,025
Admixed American	0.00192%	52,044
African / African-American	0.00137%	73,086

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: PRDM8
Protein: p.Pro574Arg
Coding: c.1721C>G
MANE Select: NM_001099403
dbSNP: rs746174564
Type: single nucleotide variant
Location: chr4:80203183 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 55.64

Full PRDM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-onset Lafora body disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For PRDM8-related progressive myoclonus epilepsy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PRDM8 p.Ala372Thr Uncertain significance ★★ ⚠ same condition
PRDM8 p.Ala416Thr Uncertain significance ★★ ⚠ same condition
PRDM8 p.Ala529Val Uncertain significance ★★ ⚠ same condition
PRDM8 p.Ala540Ser Uncertain significance ★★ ⚠ same condition
PRDM8 p.Ala541Ser Uncertain significance ★★ ⚠ same condition
PRDM8 p.Ala546Val Uncertain significance ★★ ⚠ same condition
PRDM8 p.Arg272Trp Uncertain significance ★★ ⚠ same condition
PRDM8 p.Arg448Gln Uncertain significance ★★ ⚠ 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/prdm8-p-pro574arg (accessed [today's date]).

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