Is PLOD2 p.Ala415Val (c.1244C>T) pathogenic?

PLOD2 p.Ala415Val (c.1244C>T) is classified Uncertain significance in PLOD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-22). AlphaMissense: likely pathogenic (0.7531); Very rare (popmax 8.48e-05%, nfe); Associated with Bruck syndrome 2.

What condition is associated with PLOD2 p.Ala415Val (c.1244C>T)?

PLOD2 p.Ala415Val (c.1244C>T) is associated with Bruck syndrome 2 (ClinVar).

How common is PLOD2 p.Ala415Val (c.1244C>T) in the general population?

PLOD2 p.Ala415Val (c.1244C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PLOD2 p.Ala415Val (c.1244C>T)?

AlphaMissense predicts likely pathogenic (score 0.7531) — an in-silico prediction, not a clinical call.

PLOD2 p.Ala415Val

c.1244C>T · rs1323985527 · VCV901868

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7531 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bruck syndrome 2

Computational evidence

Protein change
AlphaMissense	0.7531	likely pathogenic
REVEL	0.779	moderately pathogenic-leaning
SaProt	LLR -10.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 90 kb · p 0.85 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,178,762 alleles

Overall 6.2e-05% 1/1,612,342 alleles · very rare exomes 0/1,460,184 · genomes 1/152,158 · joint denominator

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.Ala415Val
Coding: c.1244C>T
MANE Select: NM_182943
dbSNP: rs1323985527
Type: single nucleotide variant
Location: chr3:146081852 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63
Residue 415: 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

Bruck syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLOD2 p.Arg440Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 p.Arg495Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 p.Arg680Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 c.-170C>G Uncertain significance ★★ same condition
PLOD2 p.Arg619Cys Uncertain significance ★★ ⚠ same condition
PLOD2 p.Arg648Trp Uncertain significance ★★ ⚠ same condition
PLOD2 p.Asp102Glu Uncertain significance ★★ ⚠ same condition
PLOD2 p.Glu112Gly 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-ala415val (accessed [today's date]).

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