Is EFHC1 p.Asp408Val (c.1223A>T) pathogenic?

EFHC1 p.Asp408Val (c.1223A>T) is classified Uncertain significance in EFHC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-27). AlphaMissense: ambiguous (0.4718); Ultra-rare (popmax 0.0191%, nfe); Associated with myoclonic epilepsy, juvenile, susceptibility to, 1.

What condition is associated with EFHC1 p.Asp408Val (c.1223A>T)?

EFHC1 p.Asp408Val (c.1223A>T) is associated with myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Asp408Val (c.1223A>T) in the general population?

EFHC1 p.Asp408Val (c.1223A>T) is ultra-rare (popmax 0.0191%, nfe) (gnomAD).

What do computational predictors say about EFHC1 p.Asp408Val (c.1223A>T)?

AlphaMissense predicts ambiguous (score 0.4718) — an in-silico prediction, not a clinical call.

EFHC1 p.Asp408Val

c.1223A>T · rs773810917 · VCV939704

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4718 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0191%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

myoclonic epilepsy, juvenile, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.4718	ambiguous
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -15.39	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0191% European (non-Finnish) · 225/1,179,964 alleles

Filtering AF 0.017% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0144% 232/1,613,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0191%	5,244
Remaining individualsnot grpmax-eligible	0.0112%	8,925

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.Asp408Val
Coding: c.1223A>T
MANE Select: NM_018100
dbSNP: rs773810917
Type: single nucleotide variant
Location: chr6:52469418 (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.Asp408= Benign ★★ 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-asp408val (accessed [today's date]).

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