Is EFHC1 p.Arg153Trp (c.457C>T) pathogenic?

EFHC1 p.Arg153Trp (c.457C>T) is classified Uncertain significance in EFHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-10). AlphaMissense: likely benign (0.1482); Ultra-rare (popmax 0.0114%, nfe); Associated with Absence seizure.

What condition is associated with EFHC1 p.Arg153Trp (c.457C>T)?

EFHC1 p.Arg153Trp (c.457C>T) is associated with Absence seizure, myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Arg153Trp (c.457C>T) in the general population?

EFHC1 p.Arg153Trp (c.457C>T) is ultra-rare (popmax 0.0114%, nfe) (gnomAD).

What do computational predictors say about EFHC1 p.Arg153Trp (c.457C>T)?

AlphaMissense predicts likely benign (score 0.1482) — an in-silico prediction, not a clinical call.

EFHC1 p.Arg153Trp

c.457C>T · rs373625101 · VCV846571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1482 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0114%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Absence seizure

Computational evidence

Protein change
AlphaMissense	0.1482	likely benign
REVEL	0.472	indeterminate
SaProt	LLR -13.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -0.073, phastCons 0.54
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	25.9	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 0.0114% European (non-Finnish) · 135/1,179,956 alleles

Filtering AF 0.00986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0092%

Overall 0.00905% 146/1,613,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0114%	8,740
African / African-American	0.00534%	18,724
Admixed American	0.00334%	29,973
Remaining individualsnot grpmax-eligible	0.0032%	31,233
Finnishnot grpmax-eligible	0.00313%	31,990
South Asian	0.0011%	91,078

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.Arg153Trp
Coding: c.457C>T
MANE Select: NM_018100
dbSNP: rs373625101
Type: single nucleotide variant
Location: chr6:52438475 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB
Residue 153: the dm10 1 domain; a UniProt-annotated variant site (in ejm1; uncertain significance)

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.Arg153Gln 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-arg153trp (accessed [today's date]).

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