Is EPC2 p.Pro18Arg (c.53C>G) pathogenic?

EPC2 p.Pro18Arg (c.53C>G) is classified Uncertain significance in EPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely pathogenic (0.9904); Very rare (popmax 8.6e-05%, nfe).

How common is EPC2 p.Pro18Arg (c.53C>G) in the general population?

EPC2 p.Pro18Arg (c.53C>G) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

What do computational predictors say about EPC2 p.Pro18Arg (c.53C>G)?

AlphaMissense predicts likely pathogenic (score 0.9904) — an in-silico prediction, not a clinical call.

EPC2 p.Pro18Arg

c.53C>G · VCV4249662

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9904	likely pathogenic
REVEL	0.394	indeterminate
SaProt	LLR -14.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 4.2, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 45 kb · p 1.6e-07 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.6e-05% European (non-Finnish) · 1/1,163,206 alleles

Overall 6.99e-05% 1/1,430,702 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: EPC2
Protein: p.Pro18Arg
Coding: c.53C>G
MANE Select: NM_015630
Type: single nucleotide variant
Location: chr2:148645070 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.35

Full EPC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPC2 c.666+9C>T Benign ★★ same type
EPC2 p.Arg253= Benign ★★ same type
EPC2 p.Phe6= Benign ★★ same type
EPC2 p.Ser611= Benign ★★ same type
EPC2 p.Ala13Thr Uncertain significance ★ ⚠ same type
EPC2 p.Ala14Asp Uncertain significance ★ ⚠ same type
EPC2 p.Ala634Thr Uncertain significance ★ ⚠ same type
EPC2 p.Ala711Thr Uncertain significance ★ ⚠ same type

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/epc2-p-pro18arg (accessed [today's date]).

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