Is EPC2 p.Ser488Pro (c.1462T>C) pathogenic?

EPC2 p.Ser488Pro (c.1462T>C) is classified Uncertain significance in EPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.0736); Very rare (popmax 0.00551%, nfe).

How common is EPC2 p.Ser488Pro (c.1462T>C) in the general population?

EPC2 p.Ser488Pro (c.1462T>C) is very rare (popmax 0.00551%, nfe) (gnomAD).

What do computational predictors say about EPC2 p.Ser488Pro (c.1462T>C)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

EPC2 p.Ser488Pro

c.1462T>C · VCV4018533

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00551%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.46	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 6.2	GERP 2.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 91 kb · p 6.3e-05 · regional, not allelic
Overall
CADD	20.9	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 0.00551% European (non-Finnish) · 65/1,179,840 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00403% 65/1,613,800 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.Ser488Pro
Coding: c.1462T>C
MANE Select: NM_015630
Type: single nucleotide variant
Location: chr2:148771129 (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-ser488pro (accessed [today's date]).

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