Is PEPD p.Arg431Pro (c.1292G>C) pathogenic?

PEPD p.Arg431Pro (c.1292G>C) is classified Uncertain significance in PEPD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-23). AlphaMissense: likely pathogenic (0.6264); Very rare (popmax 8.53e-05%, nfe).

How common is PEPD p.Arg431Pro (c.1292G>C) in the general population?

PEPD p.Arg431Pro (c.1292G>C) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about PEPD p.Arg431Pro (c.1292G>C)?

AlphaMissense predicts likely pathogenic (score 0.6264) — an in-silico prediction, not a clinical call.

PEPD p.Arg431Pro

c.1292G>C · rs763642654 · VCV1346656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6264 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6264	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -11.51	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.71, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 134 kb · p 0.97 · regional, not allelic
Overall
CADD	23.1	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 8.53e-05% European (non-Finnish) · 1/1,172,800 alleles

Overall 6.26e-05% 1/1,597,322 alleles · very rare exomes 0/1,445,130 · genomes 1/152,192 · joint denominator

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: PEPD
Protein: p.Arg431Pro
Coding: c.1292G>C
MANE Select: NM_000285
dbSNP: rs763642654
Type: single nucleotide variant
Location: chr19:33387942 (GRCh38)
Gene constraint: LOEUF 1.132 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.62 · 21 PDB
Residue 431: an α-helix

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

Similar variants

PEPD p.Arg431Cys Uncertain significance ★★ ⚠ same residue
PEPD p.Arg431His Uncertain significance ★★ ⚠ same residue
PEPD p.Arg431Ser Uncertain significance ★★ ⚠ same residue
PEPD p.Arg431= Likely benign ★ same residue
PEPD c.442-1G>C Pathogenic/Likely pathogenic ★★ same type
PEPD c.504-1G>A Pathogenic/Likely pathogenic ★★ same type
PEPD c.549-1G>A Pathogenic ★★ same type
PEPD c.818+2T>G Likely pathogenic ★★ 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/pepd-p-arg431pro (accessed [today's date]).

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