Is LTBP4 p.Pro746= (c.2238C>T) pathogenic?

LTBP4 p.Pro746= (c.2238C>T) is classified Benign in LTBP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 7.03%, sas) — too common for a highly-penetrant pathogenic allele; Associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies.

What condition is associated with LTBP4 p.Pro746= (c.2238C>T)?

LTBP4 p.Pro746= (c.2238C>T) is associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (ClinVar).

LTBP4 p.Pro746=

Q: How common is LTBP4 p.Pro746= (c.2238C>T) in the general population?

LTBP4 p.Pro746= (c.2238C>T) is common (popmax 7.03%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2238C>T · rs201588216 · VCV329316

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 7.03%, sas) — too common for a highly-penetrant pathogenic allele

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 -20	GERP -3.6
Overall
CADD	0.019	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.03% South Asian · 6,386/90,832 alleles

Filtering AF 6.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.83%

Overall 0.5% 8,069/1,613,270 alleles · common exomes 7,592/1,461,008 · genomes 477/152,262 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	7.03%	14
Remaining individualsnot grpmax-eligible	0.581%	172
Middle Eastern	0.462%	216
European (non-Finnish)	0.104%	961
Admixed American	0.0467%	2,141
African / African-American	0.0333%	3,000
Finnishnot grpmax-eligible	0.0156%	6,393
East Asian	0.00446%	22,430

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.Pro746=
Coding: c.2238C>T
MANE Select: NM_001042545
dbSNP: rs201588216
Type: single nucleotide variant
Location: chr19:40612131 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53
Residue 746: the egf-like 7; 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 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
LTBP4 p.Arg101His 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-pro746 (accessed [today's date]).

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