Is EPM2A p.Arg272Ser (c.814C>A) pathogenic?

EPM2A p.Arg272Ser (c.814C>A) is classified Uncertain significance in EPM2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with EPM2A p.Arg272Ser (c.814C>A)?

EPM2A p.Arg272Ser (c.814C>A) is associated with Inborn genetic diseases (ClinVar).

How common is EPM2A p.Arg272Ser (c.814C>A) in the general population?

EPM2A p.Arg272Ser (c.814C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

EPM2A p.Arg272Ser

c.814C>A · VCV4018883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.963	strongly pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 108 kb · p 0.41 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,034 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,461,882 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.Arg272Ser
Coding: c.814C>A
MANE Select: NM_005670
Type: single nucleotide variant
Location: chr6:145627598 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 34.25 · 2 PDB
Residue 272: an α-helix; a binding site; the tyrosine-protein phosphatase 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.Arg272His Uncertain significance ★★ same residue
EPM2A p.Arg272Cys Conflicting classifications of pathogenicity ★ 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

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-arg272ser (accessed [today's date]).

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