Is EFHC1 p.Ser227= (c.681A>G) pathogenic?

EFHC1 p.Ser227= (c.681A>G) is classified Likely benign in EFHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). Ultra-rare (popmax 0.0233%, amr); Associated with Absence seizure.

What condition is associated with EFHC1 p.Ser227= (c.681A>G)?

EFHC1 p.Ser227= (c.681A>G) is associated with Absence seizure, myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Ser227= (c.681A>G) in the general population?

EFHC1 p.Ser227= (c.681A>G) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

EFHC1 p.Ser227=

c.681A>G · rs772096798 · VCV702150

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Conditions

Absence seizure

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	donor loss, 20 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -3.6	GERP -3.4
Overall
CADD	3.182	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0233% Admixed American · 14/60,000 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.000867% 14/1,613,936 alleles · ultra-rare

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.Ser227=
Coding: c.681A>G
MANE Select: NM_018100
dbSNP: rs772096798
Type: single nucleotide variant
Location: chr6:52452795 (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.Ser227Leu 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
EFHC1 p.Arg151Leu 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-ser227 (accessed [today's date]).

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