Is PRDM8 p.Ser458Arg (c.1374C>A) pathogenic?

PRDM8 p.Ser458Arg (c.1374C>A) is classified Uncertain significance in PRDM8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-30). AlphaMissense: likely pathogenic (0.9866); Very rare (popmax 0.00316%, afr); Associated with early-onset Lafora body disease.

What condition is associated with PRDM8 p.Ser458Arg (c.1374C>A)?

PRDM8 p.Ser458Arg (c.1374C>A) is associated with early-onset Lafora body disease (ClinVar).

How common is PRDM8 p.Ser458Arg (c.1374C>A) in the general population?

PRDM8 p.Ser458Arg (c.1374C>A) is very rare (popmax 0.00316%, afr) (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.Ser458Arg (c.1374C>A)?

AlphaMissense predicts likely pathogenic (score 0.9866) — an in-silico prediction, not a clinical call.

PRDM8 p.Ser458Arg

c.1374C>A · rs1271340866 · VCV1020403

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00316%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-onset Lafora body disease

Computational evidence

Protein change
AlphaMissense	0.9866	likely pathogenic
REVEL	0.124	moderately benign-leaning
SaProt	LLR -10.49	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,448 bp · p 0.16 · regional, not allelic
Overall
CADD	23.8	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 0.00316% African / African-American · 2/63,316 alleles

Filtering AF 0.00155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00129%

Overall 0.00203% 25/1,229,260 alleles · very rare exomes 21/1,078,286 · genomes 4/150,974 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00316%	31,658
European (non-Finnish)	0.00232%	43,044

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.Ser458Arg
Coding: c.1374C>A
MANE Select: NM_001099403
dbSNP: rs1271340866
Type: single nucleotide variant
Location: chr4:80202836 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 55.64
Residue 458: the 'disordered' region

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-ser458arg (accessed [today's date]).

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