Is PEPD p.Asp375= (c.1125C>T) pathogenic?

PEPD p.Asp375= (c.1125C>T) is classified Conflicting classifications of pathogenicity in PEPD (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0881%, sas); Associated with prolidase deficiency.

What condition is associated with PEPD p.Asp375= (c.1125C>T)?

PEPD p.Asp375= (c.1125C>T) is associated with prolidase deficiency (ClinVar).

How common is PEPD p.Asp375= (c.1125C>T) in the general population?

PEPD p.Asp375= (c.1125C>T) is ultra-rare (popmax 0.0881%, sas) (gnomAD).

How is Prolidase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PEPD p.Asp375=

c.1125C>T · rs752440638 · VCV892558

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0881%, sas)

Conditions

prolidase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.1	GERP -4.3
Overall
CADD	1.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0881% South Asian · 80/90,770 alleles

Filtering AF 0.0725% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0668%

Overall 0.00645% 104/1,611,940 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0881%	1,135
Remaining individualsnot grpmax-eligible	0.0144%	6,940
African / African-American	0.00533%	18,758
East Asian	0.00223%	44,842
European (non-Finnish)	0.000848%	117,954

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.Asp375=
Coding: c.1125C>T
MANE Select: NM_000285
dbSNP: rs752440638
Type: single nucleotide variant
Location: chr19:33391322 (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 375: a β-strand

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

Disease context

prolidase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Prolidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal

Similar variants

PEPD c.442-1G>C Pathogenic/Likely pathogenic ★★ same condition
PEPD c.504-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEPD c.549-1G>A Pathogenic ★★ same condition
PEPD c.819-1G>A Likely pathogenic ★★ same condition
PEPD p.Ala212Pro Pathogenic/Likely pathogenic ★★ same condition
PEPD p.Arg184Ter Pathogenic ★★ same condition
PEPD p.Arg265Ter Pathogenic ★★ same condition
PEPD p.Asp276Asn Pathogenic/Likely pathogenic ★★ 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/pepd-p-asp375 (accessed [today's date]).

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