Is EFHC1 p.Arg151Cys (c.451C>T) pathogenic?

EFHC1 p.Arg151Cys (c.451C>T) is classified Likely benign in EFHC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-13). AlphaMissense: ambiguous (0.4556); Ultra-rare (popmax 0.0318%, sas); Associated with Absence seizure.

What condition is associated with EFHC1 p.Arg151Cys (c.451C>T)?

EFHC1 p.Arg151Cys (c.451C>T) is associated with Absence seizure, myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Arg151Cys (c.451C>T) in the general population?

EFHC1 p.Arg151Cys (c.451C>T) is ultra-rare (popmax 0.0318%, sas) (gnomAD).

What do computational predictors say about EFHC1 p.Arg151Cys (c.451C>T)?

AlphaMissense predicts ambiguous (score 0.4556) — an in-silico prediction, not a clinical call.

EFHC1 p.Arg151Cys

c.451C>T · rs200375854 · VCV702655

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4556 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Absence seizure

Computational evidence

Protein change
AlphaMissense	0.4556	ambiguous
REVEL	0.908	moderately pathogenic-leaning
SaProt	LLR -14.78	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 4.9	GERP 0.89, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	29.9	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 0.0318% South Asian · 29/91,078 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.0075% 121/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.145%	688
South Asiangrpmax	0.0318%	3,141
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0144%	6,944
Finnishnot grpmax-eligible	0.00781%	12,804
East Asian	0.00669%	14,959
Admixed American	0.005%	19,993
European (non-Finnish)	0.00229%	43,703
African / African-American	0.00133%	75,030

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg151Cys
Coding: c.451C>T
MANE Select: NM_018100
dbSNP: rs200375854
Type: single nucleotide variant
Location: chr6:52438469 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB
Residue 151: the dm10 1 domain

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.Arg151Leu Uncertain significance ★★ ⚠ same residue
EFHC1 p.Arg151His 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-arg151cys (accessed [today's date]).

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