Is EFHC1 p.Asp228fs (c.682_692del) pathogenic?

EFHC1 p.Asp228fs (c.682692del) is classified Uncertain significance in EFHC1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-27). Very rare (popmax 0.00627%, nfe); Associated with myoclonic epilepsy, juvenile, susceptibility to, 1.

What condition is associated with EFHC1 p.Asp228fs (c.682_692del)?

EFHC1 p.Asp228fs (c.682_692del) is associated with myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Asp228fs (c.682_692del) in the general population?

EFHC1 p.Asp228fs (c.682_692del) is very rare (popmax 0.00627%, nfe) (gnomAD).

EFHC1 p.Asp228fs

c.682_692del · rs775980459 · VCV411574

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00627%, nfe)

Conditions

myoclonic epilepsy, juvenile, susceptibility to, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00627% European (non-Finnish) · 74/1,180,034 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00496% 80/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00627%	15,946
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,001
African / African-American	0.00133%	74,924

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: EFHC1
Protein: p.Asp228fs
Coding: c.682_692del
MANE Select: NM_018100
dbSNP: rs775980459
Type: Deletion
Location: chr6:52452792 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB

Full EFHC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myoclonic epilepsy, juvenile, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EFHC1 p.Gln395fs Uncertain significance ★★ same condition
EFHC1 p.Ile367fs Uncertain significance ★★ same condition
EFHC1 p.Asp228Tyr Uncertain significance ★ ⚠ same residue
EFHC1 p.Glu391fs Uncertain significance ★ same condition
EFHC1 p.Ile122_Tyr123del Uncertain significance ★ same condition
EFHC1 c.1841_1851+13del Likely benign ★ same condition
EFHC1 c.723+66del Benign ★ same condition
EFHC1 p.Ala445Thr 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/efhc1-p-asp228fs (accessed [today's date]).

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