Is LTBP2 p.Pro753Ala (c.2257C>G) pathogenic?

LTBP2 p.Pro753Ala (c.2257C>G) is classified Uncertain significance in LTBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely benign (0.0532); Absent from gnomAD v4.1.

How common is LTBP2 p.Pro753Ala (c.2257C>G) in the general population?

LTBP2 p.Pro753Ala (c.2257C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LTBP2 p.Pro753Ala (c.2257C>G)?

AlphaMissense predicts likely benign (score 0.0532) — an in-silico prediction, not a clinical call.

LTBP2 p.Pro753Ala

c.2257C>G · rs2506153702 · VCV2087143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0532 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0532	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -5.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP -3.3, phastCons 0.097
Regional constraint	o/e 0.94	unconstrained · MANE · 107 kb · p 0.013 · regional, not allelic
Overall
CADD	1.308	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LTBP2
Protein: p.Pro753Ala
Coding: c.2257C>G
MANE Select: NM_000428
dbSNP: rs2506153702
Type: single nucleotide variant
Location: chr14:74528594 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 753: the 'disordered' region

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

Similar variants

LTBP2 p.Pro753fs Pathogenic ★ same residue
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
LTBP2 p.Arg299Ter Pathogenic ★★ same type
LTBP2 p.Cys1438Tyr 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-pro753ala (accessed [today's date]).

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