Is PLOD2 p.Arg178His (c.533G>A) pathogenic?

PLOD2 p.Arg178His (c.533G>A) is classified Conflicting classifications of pathogenicity in PLOD2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.0623); Rare (popmax 0.3%, mid); Associated with Bruck syndrome 2.

What condition is associated with PLOD2 p.Arg178His (c.533G>A)?

PLOD2 p.Arg178His (c.533G>A) is associated with Bruck syndrome 2 (ClinVar).

How common is PLOD2 p.Arg178His (c.533G>A) in the general population?

PLOD2 p.Arg178His (c.533G>A) is rare (popmax 0.3%, mid) (gnomAD).

What do computational predictors say about PLOD2 p.Arg178His (c.533G>A)?

AlphaMissense predicts likely benign (score 0.0623) — an in-silico prediction, not a clinical call.

PLOD2 p.Arg178His

c.533G>A · rs143513488 · VCV343649

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0623 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.3%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bruck syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0623	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -7.25	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 -1.1	GERP -1.7
Regional constraint	o/e 0.99	unconstrained · MANE · 90 kb · p 0.85 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.3% Middle Eastern · 18/6,006 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.16%

Overall 0.0426% 675/1,583,450 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.3%	334
European (non-Finnish)	0.0512%	1,953
Remaining individualsnot grpmax-eligible	0.0488%	2,048
African / African-American	0.0228%	4,378
Admixed American	0.0133%	7,497
South Asian	0.0111%	9,042
Finnishnot grpmax-eligible	0.00313%	31,988

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.Arg178His
Coding: c.533G>A
MANE Select: NM_182943
dbSNP: rs143513488
Type: single nucleotide variant
Location: chr3:146106614 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63
Residue 178: 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.Arg178Cys Benign/Likely benign ★★ ⚠ same residue
PLOD2 p.Arg178= Likely benign ★ same residue
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.Ala415Val Uncertain significance ★★ ⚠ same condition
PLOD2 p.Arg619Cys 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-arg178his (accessed [today's date]).

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