Is PEPD p.Phe226= (c.678C>T) pathogenic?

PEPD p.Phe226= (c.678C>T) is classified Conflicting classifications of pathogenicity in PEPD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-19). Ultra-rare (popmax 0.0123%, amr); Associated with prolidase deficiency.

What condition is associated with PEPD p.Phe226= (c.678C>T)?

PEPD p.Phe226= (c.678C>T) is associated with prolidase deficiency (ClinVar).

How common is PEPD p.Phe226= (c.678C>T) in the general population?

PEPD p.Phe226= (c.678C>T) is ultra-rare (popmax 0.0123%, amr) (gnomAD).

How is Prolidase deficiency inherited?

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

PEPD p.Phe226=

c.678C>T · rs746307467 · VCV889883

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, amr)

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 -0.52	GERP -1.6, phastCons 0.001
Overall
CADD	13.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% Admixed American · 7/56,726 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00408%

Overall 0.00272% 43/1,582,924 alleles · ultra-rare exomes 41/1,430,720 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0123%	8,104
Remaining individualsnot grpmax-eligible	0.00816%	12,248
European (non-Finnish)	0.00258%	38,754
African / African-American	0.00134%	74,360

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.Phe226=
Coding: c.678C>T
MANE Select: NM_000285
dbSNP: rs746307467
Type: single nucleotide variant
Location: chr19:33413637 (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 226: an α-helix

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 p.Phe226Leu Uncertain significance ★ ⚠ same residue
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

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-phe226 (accessed [today's date]).

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