Is EPPK1 p.Arg37fs (c.108del) pathogenic?

EPPK1 p.Arg37fs (c.108del) is classified Uncertain significance in EPPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-05). Very rare (popmax 0.00177%, amr); Associated with EPPK1-related disorder.

What condition is associated with EPPK1 p.Arg37fs (c.108del)?

EPPK1 p.Arg37fs (c.108del) is associated with EPPK1-related disorder (ClinVar).

How common is EPPK1 p.Arg37fs (c.108del) in the general population?

EPPK1 p.Arg37fs (c.108del) is very rare (popmax 0.00177%, amr) (gnomAD).

EPPK1 p.Arg37fs

c.108del · rs782106518 · VCV2636740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00177%, amr)

Conditions

EPPK1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3	GERP -2.6

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00177% Admixed American · 1/56,594 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000836% 12/1,435,144 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00508%	19,673
Ashkenazi Jewishnot grpmax-eligible	0.00361%	27,666
Admixed Americangrpmax	0.00177%	56,594
South Asian	0.00115%	87,154
European (non-Finnish)	0.000513%	194,921

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg37fs
Coding: c.108del
MANE Select: NM_031308
dbSNP: rs782106518
Type: Deletion
Location: chr8:143873146 (GRCh38)
Gene constraint: LOEUF 1.929 · pLI 0.12 (gnomAD)

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

Disease context

EPPK1-related disorder

Similar variants

EPPK1 p.Val1902fs Uncertain significance ★ same condition
EPPK1 p.Val2216fs Benign same condition
EPPK1 p.Gln2020Arg Uncertain significance ★ ⚠ same condition
EPPK1 p.Glu140Ter Uncertain significance ★ same condition
EPPK1 p.Pro35Thr Uncertain significance ★ ⚠ same condition
EPPK1 p.Val104Leu Uncertain significance ★ same condition
EPPK1 p.Ala2265= Likely benign ★ same condition
EPPK1 p.Arg2218= Likely benign ★ same condition

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-arg37fs (accessed [today's date]).

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