Is PLOD3 p.Ser346fs (c.1036dup) pathogenic?

PLOD3 p.Ser346fs (c.1036dup) is classified Pathogenic in PLOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). Very rare (popmax 0.00133%, afr).

How common is PLOD3 p.Ser346fs (c.1036dup) in the general population?

PLOD3 p.Ser346fs (c.1036dup) is very rare (popmax 0.00133%, afr) (gnomAD).

PLOD3 p.Ser346fs

c.1036dup · VCV3694254

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP 0.038, phastCons 0.002
Overall
CADD	23.3	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 0.00133% African / African-American · 1/74,908 alleles

Overall 0.000657% 1/152,150 alleles · very rare

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: PLOD3
Protein: p.Ser346fs
Coding: c.1036dup
MANE Select: NM_001084
Type: Duplication
Location: chr7:101212343 (GRCh38)
Gene constraint: LOEUF 0.925 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.80 · 18 PDB
Residue 346: the 'accessory region' region; an α-helix

Full PLOD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLOD3 p.Ser346Phe Likely benign ★★ same residue
PLOD3 p.Ala431fs Pathogenic ★ same type
PLOD3 p.Arg297fs Pathogenic ★ same type
PLOD3 p.Gln293fs Pathogenic ★ same type
PLOD3 p.Ser23fs Pathogenic ★ same type
PLOD3 p.Arg665_Pro666insGlnProSerLeuArg Uncertain significance ★ same type
PLOD3 p.Leu17_Leu18insProLeuLeu Uncertain significance ★ same type
PLOD3 c.109+6dup Likely benign ★ 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/plod3-p-ser346fs (accessed [today's date]).

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