Is EPN2 p.Ile103Phe (c.307A>T) pathogenic?

EPN2 p.Ile103Phe (c.307A>T) is classified Uncertain significance in EPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.8639); Very rare (popmax 0.00517%, nfe).

How common is EPN2 p.Ile103Phe (c.307A>T) in the general population?

EPN2 p.Ile103Phe (c.307A>T) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about EPN2 p.Ile103Phe (c.307A>T)?

AlphaMissense predicts likely pathogenic (score 0.8639) — an in-silico prediction, not a clinical call.

EPN2 p.Ile103Phe

c.307A>T · VCV4250085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8639 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8639	likely pathogenic
REVEL	0.613	indeterminate
SaProt	LLR -13.73	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 6.2	GERP 0.77, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 29 kb · p 2.8e-08 · regional, not allelic
Overall
CADD	22.7	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 0.00517% European (non-Finnish) · 61/1,180,042 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00384% 62/1,614,120 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,345
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: EPN2
Protein: p.Ile103Phe
Coding: c.307A>T
MANE Select: NM_014964
Type: single nucleotide variant
Location: chr17:19283426 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.50
Residue 103: the enth domain

Full EPN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPN2 p.Ala102Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala253Gly Uncertain significance ★ ⚠ same type
EPN2 p.Ala254Asp Uncertain significance ★ same type
EPN2 p.Ala347Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala347Val Uncertain significance ★ ⚠ same type
EPN2 p.Ala412Val Uncertain significance ★ ⚠ same type
EPN2 p.Ala428Thr Uncertain significance ★ ⚠ same type
EPN2 p.Ala428Val 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/epn2-p-ile103phe (accessed [today's date]).

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