Is LTBP2 p.Pro537Ala (c.1609C>G) pathogenic?

LTBP2 p.Pro537Ala (c.1609C>G) is classified Uncertain significance in LTBP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-27). AlphaMissense: likely benign (0.0643); Ultra-rare (popmax 0.0733%, amr); Associated with Inborn genetic diseases.

What condition is associated with LTBP2 p.Pro537Ala (c.1609C>G)?

LTBP2 p.Pro537Ala (c.1609C>G) is associated with Inborn genetic diseases (ClinVar).

How common is LTBP2 p.Pro537Ala (c.1609C>G) in the general population?

LTBP2 p.Pro537Ala (c.1609C>G) is ultra-rare (popmax 0.0733%, amr) (gnomAD).

What do computational predictors say about LTBP2 p.Pro537Ala (c.1609C>G)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

LTBP2 p.Pro537Ala

c.1609C>G · rs770862437 · VCV1431338

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0733%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.57, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 107 kb · p 0.013 · regional, not allelic
Overall
CADD	17.07	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0733% Admixed American · 44/60,014 alleles

Filtering AF 0.0561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.00285% 46/1,613,806 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0733%	1,364
European (non-Finnish)	0.000169%	590,016

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.Pro537Ala
Coding: c.1609C>G
MANE Select: NM_000428
dbSNP: rs770862437
Type: single nucleotide variant
Location: chr14:74551141 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 537: the 'disordered' 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.Pro537Thr Uncertain significance ★ ⚠ same residue
LTBP3 p.Arg537Gln Uncertain significance ★ ⚠ same residue
LTBP3 p.Arg537Trp Uncertain significance ★ ⚠ same residue
LTBP2 p.Pro537= Likely benign ★ 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

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-pro537ala (accessed [today's date]).

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