Is PEPD p.Met1Val (c.1A>G) pathogenic?

PEPD p.Met1Val (c.1A>G) is classified Pathogenic/Likely pathogenic in PEPD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-14). Ultra-rare (popmax 0.0245%, amr); Associated with PEPD-related disorder.

What condition is associated with PEPD p.Met1Val (c.1A>G)?

PEPD p.Met1Val (c.1A>G) is associated with PEPD-related disorder (ClinVar).

How common is PEPD p.Met1Val (c.1A>G) in the general population?

PEPD p.Met1Val (c.1A>G) is ultra-rare (popmax 0.0245%, amr) (gnomAD).

PEPD p.Met1Val

c.1A>G · rs752145794 · VCV1403780

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, amr)

Conditions

PEPD-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.459	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 2, phastCons 1
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% Admixed American · 14/57,222 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00513% 81/1,577,622 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0245%	4,087
African / African-American	0.0108%	9,297
South Asian	0.00577%	17,344
European (non-Finnish)	0.00454%	22,021
Ashkenazi Jewishnot grpmax-eligible	0.00345%	29,024

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000285
dbSNP: rs752145794
Type: single nucleotide variant
Location: chr19:33521760 (GRCh38)
Gene constraint: LOEUF 1.132 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.62 · 21 PDB

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

Disease context

PEPD-related disorder

Similar variants

PEPD p.Met1Arg Pathogenic/Likely pathogenic ★★ same residue
PEPD p.Met1Thr Pathogenic/Likely pathogenic ★★ same residue
PEPD c.818+2T>G Likely pathogenic ★★ same condition
PEPD p.Asp276Asn Pathogenic/Likely pathogenic ★★ same condition
PEPD p.Gly448Arg Pathogenic/Likely pathogenic ★★ same condition
PEPD p.Lys140Ter Pathogenic/Likely pathogenic ★★ same condition
PEPD p.Trp326Ter Pathogenic ★★ same condition
PEPD p.Arg314Cys 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-met1val (accessed [today's date]).

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