Is LTBP4 p.Arg375= (c.1125G>A) pathogenic?

LTBP4 p.Arg375= (c.1125G>A) is classified Benign in LTBP4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Low-frequency (popmax 3.57%, afr); Associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies.

What condition is associated with LTBP4 p.Arg375= (c.1125G>A)?

LTBP4 p.Arg375= (c.1125G>A) is associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (ClinVar).

How common is LTBP4 p.Arg375= (c.1125G>A) in the general population?

LTBP4 p.Arg375= (c.1125G>A) is low-frequency (popmax 3.57%, afr) (gnomAD).

LTBP4 p.Arg375=

c.1125G>A · rs41354044 · VCV506379

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.57%, afr)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -4
Overall
CADD	3.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.57% African / African-American · 2,680/75,048 alleles

Filtering AF 3.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.41%

Overall 0.194% 3,125/1,612,296 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.57%	28
Admixed American	0.275%	363
Remaining individualsnot grpmax-eligible	0.255%	392
Middle Eastern	0.1%	997
South Asian	0.00991%	10,095
European (non-Finnish)	0.00882%	11,341
Finnishnot grpmax-eligible	0.00315%	31,712

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.Arg375=
Coding: c.1125G>A
MANE Select: NM_001042545
dbSNP: rs41354044
Type: single nucleotide variant
Location: chr19:40607498 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53
Residue 375: the egf-like 2; calcium-binding domain; a disulfide bond

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.Arg375Gln 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-arg375 (accessed [today's date]).

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