Is PLOD1 p.Ala366Val (c.1097C>T) pathogenic?

PLOD1 p.Ala366Val (c.1097C>T) is classified Conflicting classifications of pathogenicity in PLOD1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-03-27). AlphaMissense: likely benign (0.0882); Ultra-rare (popmax 0.054%, mid); Associated with Ehlers-Danlos syndrome, kyphoscoliotic type 1.

What condition is associated with PLOD1 p.Ala366Val (c.1097C>T)?

PLOD1 p.Ala366Val (c.1097C>T) is associated with Ehlers-Danlos syndrome, kyphoscoliotic type 1, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is PLOD1 p.Ala366Val (c.1097C>T) in the general population?

PLOD1 p.Ala366Val (c.1097C>T) is ultra-rare (popmax 0.054%, mid) (gnomAD).

What do computational predictors say about PLOD1 p.Ala366Val (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.0882) — an in-silico prediction, not a clinical call.

PLOD1 p.Ala366Val

c.1097C>T · rs377080927 · VCV459802

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0882 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.054%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Computational evidence

Protein change
AlphaMissense	0.0882	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -5.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.53	GERP -2, phastCons 0.011
Regional constraint	o/e 0.93	unconstrained · MANE · 40 kb · p 0.03 · regional, not allelic
Overall
CADD	19.5	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 0.054% Middle Eastern · 3/5,560 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.0109% 175/1,612,846 alleles · ultra-rare exomes 161/1,460,606 · genomes 14/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.054%	1,853
Remaining individualsnot grpmax-eligible	0.0256%	3,903
European (non-Finnish)	0.0126%	7,919
Finnishnot grpmax-eligible	0.00631%	15,857
African / African-American	0.00267%	37,500
East Asian	0.00223%	44,868

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.Ala366Val
Coding: c.1097C>T
MANE Select: NM_000302
dbSNP: rs377080927
Type: single nucleotide variant
Location: chr1:11960767 (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.Ala366Thr Uncertain significance ★★ ⚠ same residue
PLOD1 p.Ala366Ser 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-ala366val (accessed [today's date]).

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