Is LTBP4 p.Pro651= (c.1953G>A) pathogenic?

LTBP4 p.Pro651= (c.1953G>A) is classified Benign in LTBP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.61%, sas); Associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies.

What condition is associated with LTBP4 p.Pro651= (c.1953G>A)?

LTBP4 p.Pro651= (c.1953G>A) is associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (ClinVar).

How common is LTBP4 p.Pro651= (c.1953G>A) in the general population?

LTBP4 p.Pro651= (c.1953G>A) is low-frequency (popmax 1.61%, sas) (gnomAD).

LTBP4 p.Pro651=

c.1953G>A · rs371903094 · VCV721699

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.61%, sas)

Conditions

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.3	GERP -4.3
Overall
CADD	3.382	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.61% South Asian · 1,462/90,874 alleles

Filtering AF 1.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.51%

Overall 0.0999% 1,609/1,611,112 alleles · low-frequency exomes 1,520/1,459,246 · genomes 89/151,866 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.61%	62
Remaining individualsnot grpmax-eligible	0.108%	930
Middle Eastern	0.106%	944
European (non-Finnish)	0.00577%	17,339
African / African-American	0.00401%	24,943
East Asian	0.00223%	44,776
Admixed American	0.00168%	59,638
Finnishnot grpmax-eligible	0.00157%	63,510

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: LTBP4
Protein: p.Pro651=
Coding: c.1953G>A
MANE Select: NM_001042545
dbSNP: rs371903094
Type: single nucleotide variant
Location: chr19:40611294 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53
Residue 651: the egf-like 5; calcium-binding domain

Full LTBP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LTBP4 p.Pro651Leu Uncertain significance ★ ⚠ same residue
LTBP4 c.1307-2A>G Pathogenic/Likely pathogenic ★★ same condition
LTBP4 p.Arg677Ter Pathogenic/Likely pathogenic ★★ same condition
LTBP4 c.*121C>G Uncertain significance ★★ same condition
LTBP4 p.Ala112Ser Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala124Gly Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala1342Thr Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala207Val 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/ltbp4-p-pro651 (accessed [today's date]).

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