Is PEPD p.Val135Phe (c.403G>T) pathogenic?

PEPD p.Val135Phe (c.403G>T) is classified Uncertain significance in PEPD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-05). AlphaMissense: likely benign (0.1001); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with PEPD p.Val135Phe (c.403G>T)?

PEPD p.Val135Phe (c.403G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PEPD p.Val135Phe (c.403G>T) in the general population?

PEPD p.Val135Phe (c.403G>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PEPD p.Val135Phe (c.403G>T)?

AlphaMissense predicts likely benign (score 0.1001) — an in-silico prediction, not a clinical call.

PEPD p.Val135Phe

c.403G>T · rs777913990 · VCV2073178

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1001	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -4.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.004	GERP -3, phastCons 0.001
Regional constraint	o/e 1.00	unconstrained · MANE · 134 kb · p 0.97 · regional, not allelic
Overall
CADD	5.674	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00401% African / African-American · 3/74,876 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,612,962 alleles · very rare exomes 1/1,460,846 · genomes 4/152,116 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,959
Admixed American	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,438

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.Val135Phe
Coding: c.403G>T
MANE Select: NM_000285
dbSNP: rs777913990
Type: single nucleotide variant
Location: chr19:33493328 (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 135: 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.Val135Asp Uncertain significance ★ ⚠ same residue
PEPD p.Val135Ile Conflicting classifications of pathogenicity ★ ⚠ 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

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-val135phe (accessed [today's date]).

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