Is LTBP2 p.Pro148fs (c.442_443del) pathogenic?

LTBP2 p.Pro148fs (c.442443del) is classified Pathogenic in LTBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-05). Very rare (popmax 0.00144%, afr).

How common is LTBP2 p.Pro148fs (c.442_443del) in the general population?

LTBP2 p.Pro148fs (c.442_443del) is very rare (popmax 0.00144%, afr) (gnomAD).

LTBP2 p.Pro148fs

c.442_443del · rs747161431 · VCV3004485

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00144%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 36
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.62	GERP -1.7
Overall
CADD	22.6	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 0.00144% African / African-American · 1/69,476 alleles

Overall 0.000132% 2/1,520,698 alleles · very rare exomes 0/1,368,478 · genomes 2/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00144%	69,476
European (non-Finnish)	8.72e-05%	1,146,150

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.Pro148fs
Coding: c.442_443del
MANE Select: NM_000428
dbSNP: rs747161431
Type: Deletion
Location: chr14:74611502 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 148: the 'disordered' region

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

Similar variants

LTBP3 p.Gly148Asp Uncertain significance ★★ ⚠ same residue
LTBP3 p.Pro45fs Pathogenic ★★ same type
LTBP2 p.265PQSPPA[1] Uncertain significance ★★ same type
LTBP2 p.Ala138fs Likely pathogenic ★ same type
LTBP2 p.Asn1170fs Pathogenic ★ same type
LTBP2 p.Asp325fs Pathogenic ★ same type
LTBP2 p.Asp38fs Pathogenic ★ same type
LTBP2 p.Cys1624fs 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-pro148fs (accessed [today's date]).

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