Is PEPD p.Ser142Phe (c.425C>T) pathogenic?

PEPD p.Ser142Phe (c.425C>T) is classified Uncertain significance in PEPD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-13). AlphaMissense: likely benign (0.2569); Ultra-rare (popmax 0.0393%, nfe).

How common is PEPD p.Ser142Phe (c.425C>T) in the general population?

PEPD p.Ser142Phe (c.425C>T) is ultra-rare (popmax 0.0393%, nfe) (gnomAD).

What do computational predictors say about PEPD p.Ser142Phe (c.425C>T)?

AlphaMissense predicts likely benign (score 0.2569) — an in-silico prediction, not a clinical call.

PEPD p.Ser142Phe

c.425C>T · rs375915358 · VCV1359365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2569 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0393%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2569	likely benign
REVEL	0.721	pathogenic-leaning
SaProt	LLR -12.01	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 134 kb · p 0.97 · regional, not allelic
Overall
CADD	25.1	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 0.0393% European (non-Finnish) · 463/1,179,522 alleles

Filtering AF 0.0363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.0296% 477/1,613,390 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0393%	2,548
Remaining individualsnot grpmax-eligible	0.00961%	10,410
African / African-American	0.00935%	10,698
East Asian	0.00223%	44,862

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.Ser142Phe
Coding: c.425C>T
MANE Select: NM_000285
dbSNP: rs375915358
Type: single nucleotide variant
Location: chr19:33493306 (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 142: a β-strand

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

Similar variants

PEPD p.Ser142fs Pathogenic ★ 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-ser142phe (accessed [today's date]).

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