Is EFHC1 p.Arg159Trp (c.475C>T) pathogenic?

EFHC1 p.Arg159Trp (c.475C>T) is classified Benign/Likely benign in EFHC1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0928); Common (popmax 23.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Absence seizure.

What condition is associated with EFHC1 p.Arg159Trp (c.475C>T)?

EFHC1 p.Arg159Trp (c.475C>T) is associated with Absence seizure, juvenile myoclonic epilepsy, myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

What do computational predictors say about EFHC1 p.Arg159Trp (c.475C>T)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

EFHC1 p.Arg159Trp

Q: How common is EFHC1 p.Arg159Trp (c.475C>T) in the general population?

EFHC1 p.Arg159Trp (c.475C>T) is common (popmax 23.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.475C>T · rs3804506 · VCV128968

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 23.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Absence seizure

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -9.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.11, phastCons 0.1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	19.95	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 23.2% Middle Eastern · 1,408/6,062 alleles

Filtering AF 22.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.8%

Overall 11.2% 181,436/1,613,778 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	23.2%	4
Amishnot grpmax-eligible	21.1%	5
Ashkenazi Jewishnot grpmax-eligible	14.1%	7
European (non-Finnish)	12.2%	8
Remaining individualsnot grpmax-eligible	11.1%	9
Finnishnot grpmax-eligible	10.2%	10
Admixed American	8.56%	12
South Asian	8.24%	12
African / African-American	5.51%	18
East Asian	4.23%	24

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.Arg159Trp
Coding: c.475C>T
MANE Select: NM_018100
dbSNP: rs3804506
Type: single nucleotide variant
Location: chr6:52438493 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB
Residue 159: the dm10 1 domain; a UniProt-annotated variant site (no effect on cell death; binds to cacna1e as the wild type protein; does not affect subcellular location)

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

Similar variants

EFHC1 p.Arg159Gln Uncertain significance ★★ ⚠ same residue
EFHC1 p.Arg159Gly Benign/Likely benign ★★ ⚠ 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-arg159trp (accessed [today's date]).

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