Is PEPD p.Ala205Pro (c.613G>C) pathogenic?

PEPD p.Ala205Pro (c.613G>C) is classified Uncertain significance in PEPD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely pathogenic (0.9953); Very rare (popmax 0.00399%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PEPD p.Ala205Pro (c.613G>C)?

PEPD p.Ala205Pro (c.613G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PEPD p.Ala205Pro (c.613G>C) in the general population?

PEPD p.Ala205Pro (c.613G>C) is very rare (popmax 0.00399%, nfe) (gnomAD).

What do computational predictors say about PEPD p.Ala205Pro (c.613G>C)?

AlphaMissense predicts likely pathogenic (score 0.9953) — an in-silico prediction, not a clinical call.

PEPD p.Ala205Pro

c.613G>C · VCV3887792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00399%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9953	likely pathogenic · top 2% in PEPD
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -14.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 134 kb · p 0.97 · regional, not allelic
Overall
CADD	29.2	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 0.00399% European (non-Finnish) · 47/1,177,482 alleles

Filtering AF 0.00308% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00298% 48/1,610,468 alleles · very rare exomes 48/1,458,124 · genomes 0/152,344 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00399%	25,053
Remaining individualsnot grpmax-eligible	0.0016%	62,410

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.Ala205Pro
Coding: c.613G>C
MANE Select: NM_000285
Type: single nucleotide variant
Location: chr19:33463998 (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 205: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEPD p.Ala205= Likely benign ★ same residue
PEPD p.Ala285Thr Uncertain significance ★★ ⚠ same condition
PEPD p.Arg196His Uncertain significance ★★ ⚠ same condition
PEPD p.Arg207His Uncertain significance ★★ ⚠ same condition
PEPD p.Arg233Gln Uncertain significance ★★ ⚠ same condition
PEPD p.Arg335His Uncertain significance ★★ ⚠ same condition
PEPD p.Arg388Cys Uncertain significance ★★ ⚠ same condition
PEPD p.Arg401Gln Uncertain significance ★★ ⚠ 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-ala205pro (accessed [today's date]).

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