Is EFHC1 p.Asp408= (c.1224C>T) pathogenic?

EFHC1 p.Asp408= (c.1224C>T) is classified Benign in EFHC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-15). Low-frequency (popmax 1.97%, afr); Associated with Absence seizure.

What condition is associated with EFHC1 p.Asp408= (c.1224C>T)?

EFHC1 p.Asp408= (c.1224C>T) is associated with Absence seizure, myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Asp408= (c.1224C>T) in the general population?

EFHC1 p.Asp408= (c.1224C>T) is low-frequency (popmax 1.97%, afr) (gnomAD).

EFHC1 p.Asp408=

c.1224C>T · rs116134831 · VCV128961

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.97%, afr)

Conditions

Absence seizure

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.082	GERP -0.85, phastCons 0.001
Overall
CADD	9.973	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.97% African / African-American · 1,481/75,018 alleles

Filtering AF 1.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.86%

Overall 0.148% 2,382/1,613,992 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.97%	51
Middle Eastern	0.561%	178
South Asian	0.471%	212
Remaining individualsnot grpmax-eligible	0.266%	376
Admixed American	0.175%	572
European (non-Finnish)	0.0138%	7,239
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800
Finnishnot grpmax-eligible	0.00312%	32,004

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.Asp408=
Coding: c.1224C>T
MANE Select: NM_018100
dbSNP: rs116134831
Type: single nucleotide variant
Location: chr6:52469419 (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

Absence seizure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myoclonic epilepsy, juvenile, susceptibility to, 1

Similar variants

EFHC1 p.Asp408Val Uncertain significance ★★ ⚠ same residue
EFHC1 p.Asp408fs Uncertain significance ★ same residue
EFHC1 p.Ala445Thr Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala529Glu Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala590Pro Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala83Val Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala88Val Uncertain significance ★★ ⚠ same condition
EFHC1 p.Arg118Cys 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-asp408 (accessed [today's date]).

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