Is PLOD1 p.Arg193= (c.577A>C) pathogenic?

PLOD1 p.Arg193= (c.577A>C) is classified Conflicting classifications of pathogenicity in PLOD1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-24). Rare (popmax 0.176%, sas); Associated with Ehlers-Danlos syndrome, kyphoscoliotic type 1.

What condition is associated with PLOD1 p.Arg193= (c.577A>C)?

PLOD1 p.Arg193= (c.577A>C) is associated with Ehlers-Danlos syndrome, kyphoscoliotic type 1, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is PLOD1 p.Arg193= (c.577A>C) in the general population?

PLOD1 p.Arg193= (c.577A>C) is rare (popmax 0.176%, sas) (gnomAD).

PLOD1 p.Arg193=

c.577A>C · rs569590633 · VCV292285

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.176%, sas)

Conditions

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP -0.64, phastCons 1
Overall
CADD	12.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.176% South Asian · 160/90,990 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.0103% 165/1,609,404 alleles · rare exomes 161/1,457,208 · genomes 4/152,196 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.176%	569
Middle Eastern	0.0165%	6,048
Remaining individualsnot grpmax-eligible	0.00481%	20,774
European (non-Finnish)	8.5e-05%	1,175,912

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: PLOD1
Protein: p.Arg193=
Coding: c.577A>C
MANE Select: NM_000302
dbSNP: rs569590633
Type: single nucleotide variant
Location: chr1:11952733 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.04

Full PLOD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome, kyphoscoliotic type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

PLOD1 p.Arg193Lys Uncertain significance ★ ⚠ same residue
PLOD1 p.Arg193Ser Uncertain significance ★ ⚠ same residue
PLOD1 c.1097+1G>A Pathogenic/Likely pathogenic ★★ same condition
PLOD1 c.1202+2T>C Likely pathogenic ★★ same condition
PLOD1 c.1470+2T>C Pathogenic/Likely pathogenic ★★ same condition
PLOD1 c.1471-2A>G Likely pathogenic ★★ same condition
PLOD1 c.1651-2A>G Pathogenic/Likely pathogenic ★★ same condition
PLOD1 c.168+1G>T Likely pathogenic ★★ 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/plod1-p-arg193 (accessed [today's date]).

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