Is EFHC1 p.Pro487Ser (c.1459C>T) pathogenic?

EFHC1 p.Pro487Ser (c.1459C>T) is classified Uncertain significance in EFHC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-11). AlphaMissense: likely benign (0.2692); Very rare (popmax 0.00856%, nfe); Associated with Absence seizure.

What condition is associated with EFHC1 p.Pro487Ser (c.1459C>T)?

EFHC1 p.Pro487Ser (c.1459C>T) is associated with Absence seizure, myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Pro487Ser (c.1459C>T) in the general population?

EFHC1 p.Pro487Ser (c.1459C>T) is very rare (popmax 0.00856%, nfe) (gnomAD).

What do computational predictors say about EFHC1 p.Pro487Ser (c.1459C>T)?

AlphaMissense predicts likely benign (score 0.2692) — an in-silico prediction, not a clinical call.

EFHC1 p.Pro487Ser

c.1459C>T · rs775601315 · VCV967629

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00856%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Absence seizure

Computational evidence

Protein change
AlphaMissense	0.2692	likely benign
REVEL	0.418	indeterminate
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	24.6	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 0.00856% European (non-Finnish) · 101/1,180,004 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00657% 106/1,613,928 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00856%	11,683
Finnishnot grpmax-eligible	0.00781%	12,807

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.Pro487Ser
Coding: c.1459C>T
MANE Select: NM_018100
dbSNP: rs775601315
Type: single nucleotide variant
Location: chr6:52479217 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB
Residue 487: the dm10 3 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.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-pro487ser (accessed [today's date]).

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