Is PLOD2 p.Ile252Val (c.754A>G) pathogenic?

PLOD2 p.Ile252Val (c.754A>G) is classified Uncertain significance in PLOD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-15). AlphaMissense: likely benign (0.0782); Ultra-rare (popmax 0.0331%, mid); Associated with Inborn genetic diseases.

What condition is associated with PLOD2 p.Ile252Val (c.754A>G)?

PLOD2 p.Ile252Val (c.754A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PLOD2 p.Ile252Val (c.754A>G) in the general population?

PLOD2 p.Ile252Val (c.754A>G) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about PLOD2 p.Ile252Val (c.754A>G)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

PLOD2 p.Ile252Val

c.754A>G · rs769491366 · VCV1427843

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.034	GERP 0.8, phastCons 0.006
Regional constraint	o/e 0.99	unconstrained · MANE · 90 kb · p 0.85 · regional, not allelic
Overall
CADD	2.082	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 0.0331% Middle Eastern · 2/6,046 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0035%

Overall 0.00451% 72/1,596,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,023
Remaining individualsnot grpmax-eligible	0.00808%	12,376
South Asian	0.00661%	15,123
European (non-Finnish)	0.0049%	20,416
East Asian	0.00224%	44,742
Admixed American	0.00167%	59,974

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: PLOD2
Protein: p.Ile252Val
Coding: c.754A>G
MANE Select: NM_182943
dbSNP: rs769491366
Type: single nucleotide variant
Location: chr3:146102778 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63
Residue 252: a UniProt-annotated variant site (in brks2; likely pathogenic)

Full PLOD2 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

PLOD2 p.Arg205Met Uncertain significance ★★ ⚠ same condition
PLOD2 p.Arg495Gln Uncertain significance ★★ ⚠ same condition
PLOD2 p.Asn255Ile Uncertain significance ★★ ⚠ same condition
PLOD2 p.Asp293Asn Uncertain significance ★★ ⚠ same condition
PLOD2 p.Asp316Gly Uncertain significance ★★ ⚠ same condition
PLOD2 p.Asp348Tyr Uncertain significance ★★ ⚠ same condition
PLOD2 p.Glu112Gly Uncertain significance ★★ ⚠ same condition
PLOD2 p.Gly77Asp 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/plod2-p-ile252val (accessed [today's date]).

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