Is EPPK1 p.Pro389Thr (c.1165C>A) pathogenic?

EPPK1 p.Pro389Thr (c.1165C>A) is classified Uncertain significance in EPPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0879); Ultra-rare (popmax 0.0169%, mid).

How common is EPPK1 p.Pro389Thr (c.1165C>A) in the general population?

EPPK1 p.Pro389Thr (c.1165C>A) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about EPPK1 p.Pro389Thr (c.1165C>A)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

EPPK1 p.Pro389Thr

c.1165C>A · VCV4250136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.022	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.6	GERP -3.7
Regional constraint	o/e 1.18	unconstrained · MANE · 7,913 bp · p 8.9e-24 · regional, not allelic
Overall
CADD	2.416	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 0.0169% Middle Eastern · 1/5,908 alleles

Filtering AF 0.00245% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00214%

Overall 0.00339% 53/1,562,192 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,908
Remaining individualsnot grpmax-eligible	0.0149%	6,720
Admixed American	0.00575%	17,397
European (non-Finnish)	0.00329%	30,355
African / African-American	0.00271%	36,833

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: EPPK1
Protein: p.Pro389Thr
Coding: c.1165C>A
MANE Select: NM_031308
Type: single nucleotide variant
Location: chr8:143872089 (GRCh38)
Gene constraint: LOEUF 1.929 · pLI 0.12 (gnomAD)
Residue 389: the 'interaction with krt5' region

Full EPPK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPPK1 p.Gly716Ser Uncertain significance ★★ same type
EPPK1 p.Gly441Ser Benign/Likely benign ★★ same type
EPPK1 p.Ala1025Thr Uncertain significance ★ same type
EPPK1 p.Ala1076Val Uncertain significance ★ ⚠ same type
EPPK1 p.Ala1119Val Uncertain significance ★ ⚠ same type
EPPK1 p.Ala1138Val Uncertain significance ★ ⚠ same type
EPPK1 p.Ala118Thr Uncertain significance ★ same type
EPPK1 p.Ala1205Thr 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/eppk1-p-pro389thr (accessed [today's date]).

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