Is PRDM8 p.Phe227Ile (c.679T>A) pathogenic?

PRDM8 p.Phe227Ile (c.679T>A) is classified Uncertain significance in PRDM8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.3155); Very rare (popmax 0.00595%, nfe); Associated with early-onset Lafora body disease.

What condition is associated with PRDM8 p.Phe227Ile (c.679T>A)?

PRDM8 p.Phe227Ile (c.679T>A) is associated with early-onset Lafora body disease (ClinVar).

How common is PRDM8 p.Phe227Ile (c.679T>A) in the general population?

PRDM8 p.Phe227Ile (c.679T>A) is very rare (popmax 0.00595%, 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.Phe227Ile (c.679T>A)?

AlphaMissense predicts likely benign (score 0.3155) — an in-silico prediction, not a clinical call.

PRDM8 p.Phe227Ile

c.679T>A · rs768596814 · VCV863656

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3155 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00595%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-onset Lafora body disease

Computational evidence

Protein change
AlphaMissense	0.3155	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,448 bp · p 0.16 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00595% European (non-Finnish) · 70/1,177,358 alleles

Filtering AF 0.00479% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00456% 73/1,602,298 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00595%	16,819
Remaining individualsnot grpmax-eligible	0.00321%	31,150
African / African-American	0.00142%	70,584

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.Phe227Ile
Coding: c.679T>A
MANE Select: NM_001099403
dbSNP: rs768596814
Type: single nucleotide variant
Location: chr4:80202141 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 55.64
Residue 227: 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-phe227ile (accessed [today's date]).

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