Is LTBP4 p.Pro58Ser (c.172C>T) pathogenic?

LTBP4 p.Pro58Ser (c.172C>T) is classified Uncertain significance in LTBP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0787); Ultra-rare (popmax 0.0133%, afr); Associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies.

What condition is associated with LTBP4 p.Pro58Ser (c.172C>T)?

LTBP4 p.Pro58Ser (c.172C>T) is associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (ClinVar).

How common is LTBP4 p.Pro58Ser (c.172C>T) in the general population?

LTBP4 p.Pro58Ser (c.172C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about LTBP4 p.Pro58Ser (c.172C>T)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

LTBP4 p.Pro58Ser

c.172C>T · rs373445028 · VCV1302535

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -6.97	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 3.6	GERP 1.4, phastCons 0.9
Overall
CADD	12.65	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P95S vs ClinVar P58S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/75,040 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.000806% 13/1,613,608 alleles · ultra-rare exomes 6/1,461,322 · genomes 7/152,286 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.00017%	589,936

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.Pro58Ser
Coding: c.172C>T
MANE Select: NM_001042545 · reported on NM_003573
dbSNP: rs373445028
Type: single nucleotide variant
Location: chr19:40599498 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53

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-pro58ser (accessed [today's date]).

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