Is EFHC1 p.Ala83Val (c.248C>T) pathogenic?

EFHC1 p.Ala83Val (c.248C>T) is classified Uncertain significance in EFHC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-24). AlphaMissense: likely benign (0.0862); Very rare (popmax 0.00439%, sas); Associated with Absence seizure.

What condition is associated with EFHC1 p.Ala83Val (c.248C>T)?

EFHC1 p.Ala83Val (c.248C>T) is associated with Absence seizure, myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Ala83Val (c.248C>T) in the general population?

EFHC1 p.Ala83Val (c.248C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about EFHC1 p.Ala83Val (c.248C>T)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

EFHC1 p.Ala83Val

c.248C>T · rs557599173 · VCV840601

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Absence seizure

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 1.8, phastCons 0.53
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	18.25	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 0.00439% South Asian · 4/91,078 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00116% 17/1,461,814 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,769
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00102%	98,330

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.Ala83Val
Coding: c.248C>T
MANE Select: NM_018100
dbSNP: rs557599173
Type: single nucleotide variant
Location: chr6:52424130 (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

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.Ala83= 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.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-ala83val (accessed [today's date]).

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