Is EFHC1 p.Ala529= (c.1587G>A) pathogenic?

EFHC1 p.Ala529= (c.1587G>A) is classified Conflicting classifications of pathogenicity in EFHC1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-28). Ultra-rare (popmax 0.02%, nfe); Associated with myoclonic epilepsy, juvenile, susceptibility to, 1.

What condition is associated with EFHC1 p.Ala529= (c.1587G>A)?

EFHC1 p.Ala529= (c.1587G>A) is associated with myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Ala529= (c.1587G>A) in the general population?

EFHC1 p.Ala529= (c.1587G>A) is ultra-rare (popmax 0.02%, nfe) (gnomAD).

EFHC1 p.Ala529=

c.1587G>A · rs377227885 · VCV137196

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, 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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -4.5
Overall
CADD	4.785	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% European (non-Finnish) · 236/1,180,038 alleles

Filtering AF 0.0179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.0159% 256/1,614,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.02%	5,000
Remaining individualsnot grpmax-eligible	0.0128%	7,810
Finnishnot grpmax-eligible	0.00937%	10,669
African / African-American	0.00534%	18,726
East Asian	0.00223%	44,902
Admixed American	0.00167%	60,002

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.Ala529=
Coding: c.1587G>A
MANE Select: NM_018100
dbSNP: rs377227885
Type: single nucleotide variant
Location: chr6:52479734 (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.Ala529Glu Uncertain significance ★★ ⚠ same residue
EFHC1 p.Ala529Thr Uncertain significance ★ ⚠ same residue
EFHC1 p.Ala445Thr 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-ala529 (accessed [today's date]).

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