Is EPC2 p.Phe378Leu (c.1132T>C) pathogenic?

EPC2 p.Phe378Leu (c.1132T>C) is classified Uncertain significance in EPC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: ambiguous (0.503); Absent from gnomAD v4.1.

How common is EPC2 p.Phe378Leu (c.1132T>C) in the general population?

EPC2 p.Phe378Leu (c.1132T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPC2 p.Phe378Leu (c.1132T>C)?

AlphaMissense predicts ambiguous (score 0.503) — an in-silico prediction, not a clinical call.

EPC2 p.Phe378Leu

c.1132T>C · VCV4018543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.503 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,546,326)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.503	ambiguous
REVEL	0.095	moderately benign-leaning
SaProt	LLR -4.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 91 kb · p 6.3e-05 · regional, not allelic
Overall
CADD	21.3	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

No allele count reported in gnomAD v4.1 (AN 1,546,326). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: EPC2
Protein: p.Phe378Leu
Coding: c.1132T>C
MANE Select: NM_015630
Type: single nucleotide variant
Location: chr2:148765138 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.35
Residue 378: the 'disordered' region

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-phe378leu (accessed [today's date]).

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