Is PEPD p.Arg331Cys (c.991C>T) pathogenic?

PEPD p.Arg331Cys (c.991C>T) is classified Uncertain significance in PEPD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely benign (0.1756); Very rare (popmax 0.00682%, afr).

How common is PEPD p.Arg331Cys (c.991C>T) in the general population?

PEPD p.Arg331Cys (c.991C>T) is very rare (popmax 0.00682%, afr) (gnomAD).

What do computational predictors say about PEPD p.Arg331Cys (c.991C>T)?

AlphaMissense predicts likely benign (score 0.1756) — an in-silico prediction, not a clinical call.

PEPD p.Arg331Cys

c.991C>T · rs376817734 · VCV2140709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00682%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1756	likely benign
REVEL	0.642	indeterminate
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 134 kb · p 0.97 · regional, not allelic
Overall
CADD	33.0	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 0.00682% African / African-American · 5/73,272 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00165%

Overall 0.00193% 30/1,552,866 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00682%	14,654
South Asian	0.00355%	28,130
East Asian	0.00243%	41,198
European (non-Finnish)	0.00183%	54,697

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.Arg331Cys
Coding: c.991C>T
MANE Select: NM_000285
dbSNP: rs376817734
Type: single nucleotide variant
Location: chr19:33391456 (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 331: an α-helix

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

Similar variants

PEPD p.Arg331His Uncertain significance ★ ⚠ same residue
PEPD p.Arg331Leu Uncertain significance ★ ⚠ same residue
PEPD p.Arg331Ser Uncertain significance ★ ⚠ 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
PEPD c.819-1G>A 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-arg331cys (accessed [today's date]).

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