Is EPM2A p.Pro78Arg (c.233C>G) pathogenic?

EPM2A p.Pro78Arg (c.233C>G) is classified Uncertain significance in EPM2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). Very rare (popmax 0.000177%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EPM2A p.Pro78Arg (c.233C>G)?

EPM2A p.Pro78Arg (c.233C>G) is associated with Inborn genetic diseases (ClinVar).

How common is EPM2A p.Pro78Arg (c.233C>G) in the general population?

EPM2A p.Pro78Arg (c.233C>G) is very rare (popmax 0.000177%, nfe) (gnomAD).

EPM2A p.Pro78Arg

c.233C>G · VCV3845522

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000177%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.64	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.81, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 108 kb · p 0.41 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000177% European (non-Finnish) · 2/1,131,326 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000146% 2/1,366,016 alleles · very rare

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: EPM2A
Protein: p.Pro78Arg
Coding: c.233C>G
MANE Select: NM_005670
Type: single nucleotide variant
Location: chr6:145735266 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 34.25 · 2 PDB
Residue 78: the 'disordered' region; the cbm20 domain

Full EPM2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPM2A p.Pro78= Likely benign ★ same residue
EPM2A c.301+5T>G Uncertain significance ★★ same condition
EPM2A p.Ala268Thr Uncertain significance ★★ same condition
EPM2A p.Ala71Glu Uncertain significance ★★ same condition
EPM2A p.Arg26Leu Uncertain significance ★★ same condition
EPM2A p.Asn137Ser Uncertain significance ★★ same condition
EPM2A p.Asn163Ser Uncertain significance ★★ same condition
EPM2A p.Glu239Val 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/epm2a-p-pro78arg (accessed [today's date]).

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