Is EPPK1 p.Ala40Pro (c.118G>C) pathogenic?

EPPK1 p.Ala40Pro (c.118G>C) is classified Uncertain significance in EPPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). AlphaMissense: likely benign (0.1171); Ultra-rare (popmax 0.0169%, mid).

How common is EPPK1 p.Ala40Pro (c.118G>C) in the general population?

EPPK1 p.Ala40Pro (c.118G>C) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about EPPK1 p.Ala40Pro (c.118G>C)?

AlphaMissense predicts likely benign (score 0.1171) — an in-silico prediction, not a clinical call.

EPPK1 p.Ala40Pro

c.118G>C · VCV4250174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1171 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1171	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.13	GERP 0.19
Regional constraint	o/e 1.18	unconstrained · MANE · 7,913 bp · p 8.9e-24 · regional, not allelic
Overall
CADD	15.46	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Middle Eastern · 1/5,926 alleles

Overall 0.000126% 2/1,583,596 alleles · ultra-rare exomes 1/1,431,362 · genomes 1/152,234 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,926
European (non-Finnish)	8.56e-05%	1,168,136

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.Ala40Pro
Coding: c.118G>C
MANE Select: NM_031308
Type: single nucleotide variant
Location: chr8:143873136 (GRCh38)
Gene constraint: LOEUF 1.929 · pLI 0.12 (gnomAD)

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

Similar variants

EPPK1 p.Ala40Thr Uncertain significance ★ ⚠ same residue
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

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-ala40pro (accessed [today's date]).

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