Is LTBP2 p.Arg548Ter (c.1642C>T) pathogenic?

LTBP2 p.Arg548Ter (c.1642C>T) is classified Pathogenic in LTBP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-17). Very rare (popmax 0.0022%, sas); Associated with Marfan syndrome.

What condition is associated with LTBP2 p.Arg548Ter (c.1642C>T)?

LTBP2 p.Arg548Ter (c.1642C>T) is associated with Marfan syndrome (ClinVar).

How common is LTBP2 p.Arg548Ter (c.1642C>T) in the general population?

LTBP2 p.Arg548Ter (c.1642C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Marfan syndrome inherited?

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

LTBP2 p.Arg548Ter

c.1642C>T · rs137854855 · VCV126952

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Marfan syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 36
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.28	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.4	GERP 0.54, phastCons 0.98
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000137% 2/1,461,498 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: LTBP2
Protein: p.Arg548Ter
Coding: c.1642C>T
MANE Select: NM_000428
dbSNP: rs137854855
Type: single nucleotide variant
Location: chr14:74551108 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33

Full LTBP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Marfan syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

LTBP2 p.Arg548Gly Uncertain significance ★ ⚠ same residue
LTBP3 p.Pro548Thr Uncertain significance ★ ⚠ same residue
LTBP2 c.4720+7G>A Uncertain significance same condition
LTBP2 c.2389-2A>G Likely pathogenic ★★ same type
LTBP2 c.2659+2T>C Likely pathogenic ★★ same type
LTBP2 c.2789-1G>A Likely pathogenic ★★ same type
LTBP2 c.2789-2A>T Likely pathogenic ★★ same type
LTBP2 c.3652+1G>A Likely pathogenic ★★ same type

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/ltbp2-p-arg548ter (accessed [today's date]).

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