Is EFHC1 p.Asp408fs (c.1221dup) pathogenic?

EFHC1 p.Asp408fs (c.1221dup) is classified Uncertain significance in EFHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-11-19). Very rare (popmax 0.00535%, afr); Associated with myoclonic epilepsy, juvenile, susceptibility to, 1.

What condition is associated with EFHC1 p.Asp408fs (c.1221dup)?

EFHC1 p.Asp408fs (c.1221dup) is associated with myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Asp408fs (c.1221dup) in the general population?

EFHC1 p.Asp408fs (c.1221dup) is very rare (popmax 0.00535%, afr) (gnomAD).

EFHC1 p.Asp408fs

c.1221dup · rs754483740 · VCV411571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

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 7 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, 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 0.00535% African / African-American · 4/74,810 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000496% 8/1,613,634 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,702
South Asian	0.0011%	91,066
European (non-Finnish)	0.000254%	393,301

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.Asp408fs
Coding: c.1221dup
MANE Select: NM_018100
dbSNP: rs754483740
Type: Duplication
Location: chr6:52469409 (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.Asp408Val Uncertain significance ★★ ⚠ same residue
EFHC1 p.Asp408= Benign ★★ same residue
EFHC1 p.Ile430fs Uncertain significance ★★ same condition
EFHC1 p.Lys222Ter Uncertain significance ★ same condition
EFHC1 p.Thr478fs Uncertain significance ★ same condition
EFHC1 p.Ala445Thr Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala529Glu Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala590Pro 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-asp408fs (accessed [today's date]).

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