Is PRDM8 p.Pro613Arg (c.1838C>G) pathogenic?

PRDM8 p.Pro613Arg (c.1838C>G) is classified Uncertain significance in PRDM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: likely pathogenic (0.9926); Very rare (popmax 0.000339%, nfe); Associated with early-onset Lafora body disease.

What condition is associated with PRDM8 p.Pro613Arg (c.1838C>G)?

PRDM8 p.Pro613Arg (c.1838C>G) is associated with early-onset Lafora body disease (ClinVar).

How common is PRDM8 p.Pro613Arg (c.1838C>G) in the general population?

PRDM8 p.Pro613Arg (c.1838C>G) is very rare (popmax 0.000339%, 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.Pro613Arg (c.1838C>G)?

AlphaMissense predicts likely pathogenic (score 0.9926) — an in-silico prediction, not a clinical call.

PRDM8 p.Pro613Arg

c.1838C>G · rs1553906552 · VCV475675

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-onset Lafora body disease

Computational evidence

Protein change
AlphaMissense	0.9926	likely pathogenic · top 10% in PRDM8
REVEL	0.646	pathogenic-leaning
SaProt	LLR -13.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.66, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,448 bp · p 0.16 · regional, not allelic
Overall
CADD	29.0	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 0.000339% European (non-Finnish) · 4/1,179,098 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,610,716 alleles · very rare exomes 5/1,458,454 · genomes 0/152,262 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,310
European (non-Finnish)grpmax	0.000339%	294,775

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro613Arg
Coding: c.1838C>G
MANE Select: NM_001099403
dbSNP: rs1553906552
Type: single nucleotide variant
Location: chr4:80203300 (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.Pro613= Likely benign ★ same residue
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

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-pro613arg (accessed [today's date]).

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