Is PLOD3 p.Val538= (c.1614C>T) pathogenic?

PLOD3 p.Val538= (c.1614C>T) is classified Conflicting classifications of pathogenicity in PLOD3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-12-01). Ultra-rare (popmax 0.0658%, mid); Associated with Inborn genetic diseases.

What condition is associated with PLOD3 p.Val538= (c.1614C>T)?

PLOD3 p.Val538= (c.1614C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLOD3 p.Val538= (c.1614C>T) in the general population?

PLOD3 p.Val538= (c.1614C>T) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

PLOD3 p.Val538=

c.1614C>T · rs148949172 · VCV1510929

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.345	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.87	GERP -8.4, phastCons 0.003
Overall
CADD	2.036	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0658% Middle Eastern · 4/6,080 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0436%

Overall 0.0405% 653/1,611,798 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0703%	1,423
Middle Easterngrpmax	0.0658%	1,520
European (non-Finnish)	0.0482%	2,074
Remaining individualsnot grpmax-eligible	0.0321%	3,120
Admixed American	0.0167%	5,999
African / African-American	0.00534%	18,725
East Asian	0.00223%	44,890
South Asian	0.0011%	90,996

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val538=
Coding: c.1614C>T
MANE Select: NM_001084
dbSNP: rs148949172
Type: single nucleotide variant
Location: chr7:101210331 (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 538: an α-helix; a UniProt-annotated variant site (in bcard; uncertain significance)

Full PLOD3 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

PLOD3 c.338+6G>C Uncertain significance ★★ same condition
PLOD3 p.Ala59Val Uncertain significance ★★ ⚠ same condition
PLOD3 p.Ala646Val Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg135His Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg181His Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg313His Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg317Gln Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg551Trp 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/plod3-p-val538 (accessed [today's date]).

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