Is PEPD p.Ala2Val (c.5C>T) pathogenic?

PEPD p.Ala2Val (c.5C>T) is classified Uncertain significance in PEPD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-26). AlphaMissense: ambiguous (0.4529); Very rare (popmax 0.00463%, eas).

How common is PEPD p.Ala2Val (c.5C>T) in the general population?

PEPD p.Ala2Val (c.5C>T) is very rare (popmax 0.00463%, eas) (gnomAD).

What do computational predictors say about PEPD p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.4529) — an in-silico prediction, not a clinical call.

PEPD p.Ala2Val

c.5C>T · VCV4755110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00463%, eas)

Computational evidence

Protein change
AlphaMissense	0.4529	ambiguous
REVEL	0.496	indeterminate
SaProt	LLR -9.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 134 kb · p 0.97 · regional, not allelic
Overall
CADD	28.0	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 0.00463% East Asian · 2/43,222 alleles

Filtering AF 0.000767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000287%

Overall 0.000824% 13/1,577,296 alleles · very rare exomes 11/1,425,068 · genomes 2/152,228 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00463%	21,611
Finnishnot grpmax-eligible	0.00375%	26,683
Remaining individualsnot grpmax-eligible	0.00164%	61,128
African / African-American	0.00135%	74,298
European (non-Finnish)	0.0006%	166,720

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_000285
Type: single nucleotide variant
Location: chr19:33521756 (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 2: a modified residue (n-acetylalanine)

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

Similar variants

PEPD p.Ala2= 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
PEPD p.Arg184Ter 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-ala2val (accessed [today's date]).

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