Is EFHC1 p.Val192Ile (c.574G>A) pathogenic?

EFHC1 p.Val192Ile (c.574G>A) is classified Uncertain significance in EFHC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0817); Ultra-rare (popmax 0.0136%, nfe); Associated with myoclonic epilepsy, juvenile, susceptibility to, 1.

What condition is associated with EFHC1 p.Val192Ile (c.574G>A)?

EFHC1 p.Val192Ile (c.574G>A) is associated with myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Val192Ile (c.574G>A) in the general population?

EFHC1 p.Val192Ile (c.574G>A) is ultra-rare (popmax 0.0136%, nfe) (gnomAD).

What do computational predictors say about EFHC1 p.Val192Ile (c.574G>A)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

EFHC1 p.Val192Ile

c.574G>A · rs781665913 · VCV205382

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myoclonic epilepsy, juvenile, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.6	GERP 0.052, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	18.77	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0136% European (non-Finnish) · 160/1,179,948 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.0101% 163/1,613,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0136%	7,375
Remaining individualsnot grpmax-eligible	0.0032%	31,238
Finnishnot grpmax-eligible	0.00156%	63,996

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.Val192Ile
Coding: c.574G>A
MANE Select: NM_018100
dbSNP: rs781665913
Type: single nucleotide variant
Location: chr6:52452688 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB
Residue 192: the dm10 1 domain

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.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
EFHC1 p.Arg159Gln 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-val192ile (accessed [today's date]).

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