Is LTBP2 p.Arg1652Pro (c.4955G>C) pathogenic?

LTBP2 p.Arg1652Pro (c.4955G>C) is classified Uncertain significance in LTBP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: ambiguous (0.449); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LTBP2 p.Arg1652Pro (c.4955G>C)?

LTBP2 p.Arg1652Pro (c.4955G>C) is associated with Inborn genetic diseases (ClinVar).

How common is LTBP2 p.Arg1652Pro (c.4955G>C) in the general population?

LTBP2 p.Arg1652Pro (c.4955G>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about LTBP2 p.Arg1652Pro (c.4955G>C)?

AlphaMissense predicts ambiguous (score 0.449) — an in-silico prediction, not a clinical call.

LTBP2 p.Arg1652Pro

c.4955G>C · rs773510546 · VCV2850342

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.449 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.449	ambiguous
REVEL	0.457	indeterminate
SaProt	LLR -4.72	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 3,963 bp · p 0.0091 · regional, not allelic
Overall
CADD	24.7	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 0.000678% European (non-Finnish) · 8/1,180,038 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,828 alleles · very rare exomes 8/1,461,516 · genomes 0/152,312 · joint denominator

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.Arg1652Pro
Coding: c.4955G>C
MANE Select: NM_000428
dbSNP: rs773510546
Type: single nucleotide variant
Location: chr14:74502868 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 1652: the 'c-terminal domain' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LTBP2 p.Arg1652Trp Uncertain significance ★★ ⚠ same residue
LTBP2 p.Arg1652Gln Uncertain significance ★ ⚠ same residue
LTBP2 p.Arg1652Leu Uncertain significance ★ ⚠ same residue
LTBP2 p.Ala1204Thr Uncertain significance ★★ ⚠ same condition
LTBP2 p.Ala1354Val Uncertain significance ★★ same condition
LTBP2 p.Ala1359Val Uncertain significance ★★ same condition
LTBP2 p.Ala141Gly Uncertain significance ★★ ⚠ same condition
LTBP2 p.Ala1421Val 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/ltbp2-p-arg1652pro (accessed [today's date]).

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