Is PLOD1 p.Ala640Val (c.1919C>T) pathogenic?

PLOD1 p.Ala640Val (c.1919C>T) is classified Uncertain significance in PLOD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.8466); Very rare (popmax 0.000424%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with PLOD1 p.Ala640Val (c.1919C>T)?

PLOD1 p.Ala640Val (c.1919C>T) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is PLOD1 p.Ala640Val (c.1919C>T) in the general population?

PLOD1 p.Ala640Val (c.1919C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about PLOD1 p.Ala640Val (c.1919C>T)?

AlphaMissense predicts likely pathogenic (score 0.8466) — an in-silico prediction, not a clinical call.

PLOD1 p.Ala640Val

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1919C>T · VCV3420931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8466 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.8466	likely pathogenic
REVEL	0.53	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -0.99, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 40 kb · p 0.03 · regional, not allelic
Overall
CADD	25.6	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 0.000424% European (non-Finnish) · 5/1,179,952 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,784 alleles · very rare

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.Ala640Val
Coding: c.1919C>T
MANE Select: NM_000302
Type: single nucleotide variant
Location: chr1:11972888 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.04
Residue 640: the fe2og dioxygenase domain

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

PLOD1 c.1097+1G>A 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.467-2A>G Likely pathogenic ★★ same condition
PLOD1 p.Ala667Thr Likely pathogenic ★★ same condition
PLOD1 p.Gln56Ter Pathogenic ★★ same condition
PLOD1 p.Tyr511Ter Pathogenic ★★ same condition
PLOD1 c.741+4G>C 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/plod1-p-ala640val (accessed [today's date]).

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