Is EPPK1 p.Arg412Trp (c.1234C>T) pathogenic?

EPPK1 p.Arg412Trp (c.1234C>T) is classified Benign in EPPK1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-20). AlphaMissense: likely benign (0.2563); Low-frequency (popmax 1.26%, nfe); Associated with EPPK1-related disorder.

What condition is associated with EPPK1 p.Arg412Trp (c.1234C>T)?

EPPK1 p.Arg412Trp (c.1234C>T) is associated with EPPK1-related disorder (ClinVar).

How common is EPPK1 p.Arg412Trp (c.1234C>T) in the general population?

EPPK1 p.Arg412Trp (c.1234C>T) is low-frequency (popmax 1.26%, nfe) (gnomAD).

What do computational predictors say about EPPK1 p.Arg412Trp (c.1234C>T)?

AlphaMissense predicts likely benign (score 0.2563) — an in-silico prediction, not a clinical call.

EPPK1 p.Arg412Trp

c.1234C>T · rs140364895 · VCV3052534

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2563 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.26%, nfe)

Conditions

EPPK1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2563	likely benign
REVEL	0.595	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.66, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 7,913 bp · p 8.9e-24 · regional, not allelic
Overall
CADD	22.7	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

Grpmax group 1.26% European (non-Finnish) · 14,534/1,157,634 alleles

Filtering AF 1.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.23%

Overall 1.11% 17,339/1,565,312 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.77%	36
European (non-Finnish)grpmax	1.26%	80
Middle Eastern	1.09%	91
Remaining individualsnot grpmax-eligible	0.921%	109
Admixed American	0.677%	148
Ashkenazi Jewishnot grpmax-eligible	0.454%	220
African / African-American	0.182%	548
South Asian	0.0346%	2,888
East Asian	0.00236%	42,388

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.Arg412Trp
Coding: c.1234C>T
MANE Select: NM_031308
dbSNP: rs140364895
Type: single nucleotide variant
Location: chr8:143872020 (GRCh38)
Gene constraint: LOEUF 1.929 · pLI 0.12 (gnomAD)
Residue 412: the 'interaction with krt5' region

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

Disease context

EPPK1-related disorder

Similar variants

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
EPPK1 p.Arg2305= Likely benign ★ same condition
EPPK1 p.Arg2356= 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-arg412trp (accessed [today's date]).

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