Is EFHC1 p.Pro77Thr (c.229C>A) pathogenic?

EFHC1 p.Pro77Thr (c.229C>A) is classified Benign/Likely benign in EFHC1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-04-14). AlphaMissense: likely benign (0.0766); Low-frequency (popmax 2.46%, afr); Associated with Absence seizure.

What condition is associated with EFHC1 p.Pro77Thr (c.229C>A)?

EFHC1 p.Pro77Thr (c.229C>A) is associated with Absence seizure, myoclonic epilepsy, juvenile, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Pro77Thr (c.229C>A) in the general population?

EFHC1 p.Pro77Thr (c.229C>A) is low-frequency (popmax 2.46%, afr) (gnomAD).

What do computational predictors say about EFHC1 p.Pro77Thr (c.229C>A)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

EFHC1 p.Pro77Thr

c.229C>A · rs149055334 · VCV205400

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.46%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Absence seizure

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -6.73	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 0.13	GERP -0.14
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	10.48	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 2.46% African / African-American · 1,846/75,008 alleles

Filtering AF 2.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.33%

Overall 0.13% 2,103/1,614,090 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.46%	41
Admixed American	0.225%	445
Remaining individualsnot grpmax-eligible	0.152%	658
Middle Eastern	0.0495%	2,019
European (non-Finnish)	0.00195%	51,305
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.Pro77Thr
Coding: c.229C>A
MANE Select: NM_018100
dbSNP: rs149055334
Type: single nucleotide variant
Location: chr6:52424111 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB
Residue 77: a UniProt-annotated variant site (in ejm1; associated in cis with h-221; reduces substantially the cell death effect; reduces partly the calcium influx; binds to cacna1e)

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-pro77thr (accessed [today's date]).

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