Is PEPD p.Arg33Trp (c.97C>T) pathogenic?

PEPD p.Arg33Trp (c.97C>T) is classified Uncertain significance in PEPD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: ambiguous (0.4794); Ultra-rare (popmax 0.0175%, nfe).

How common is PEPD p.Arg33Trp (c.97C>T) in the general population?

PEPD p.Arg33Trp (c.97C>T) is ultra-rare (popmax 0.0175%, nfe) (gnomAD).

What do computational predictors say about PEPD p.Arg33Trp (c.97C>T)?

AlphaMissense predicts ambiguous (score 0.4794) — an in-silico prediction, not a clinical call.

PEPD p.Arg33Trp

c.97C>T · rs61734503 · VCV1443595

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4794	ambiguous
REVEL	0.729	pathogenic-leaning
SaProt	LLR -14.05	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP -0.27, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 134 kb · p 0.97 · regional, not allelic
Overall
CADD	25.5	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 0.0175% European (non-Finnish) · 207/1,179,914 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.0134% 216/1,613,838 alleles · ultra-rare exomes 204/1,461,634 · genomes 12/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0175%	5,700
African / African-American	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.0048%	20,823
South Asian	0.0011%	91,092

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.Arg33Trp
Coding: c.97C>T
MANE Select: NM_000285
dbSNP: rs61734503
Type: single nucleotide variant
Location: chr19:33512697 (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 33: an α-helix

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

Similar variants

PEPD p.Arg33Gln Uncertain significance ★ ⚠ same residue
PEPD p.Arg33= 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
PEPD c.819-1G>A Likely pathogenic ★★ same type
PEPD p.Ala212Pro Pathogenic/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-arg33trp (accessed [today's date]).

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