Is LTBP4 p.Val95Ala (c.284T>C) pathogenic?

LTBP4 p.Val95Ala (c.284T>C) is classified Uncertain significance in LTBP4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-02). AlphaMissense: ambiguous (0.5464); Ultra-rare (popmax 0.0709%, nfe); Associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies.

What condition is associated with LTBP4 p.Val95Ala (c.284T>C)?

LTBP4 p.Val95Ala (c.284T>C) is associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (ClinVar).

How common is LTBP4 p.Val95Ala (c.284T>C) in the general population?

LTBP4 p.Val95Ala (c.284T>C) is ultra-rare (popmax 0.0709%, nfe) (gnomAD).

What do computational predictors say about LTBP4 p.Val95Ala (c.284T>C)?

AlphaMissense predicts ambiguous (score 0.5464) — an in-silico prediction, not a clinical call.

LTBP4 p.Val95Ala

c.284T>C · rs200888669 · VCV450016

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5464 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0709%, nfe)

Conditions

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Computational evidence

Protein change
AlphaMissense	0.5464	ambiguous
REVEL	0.441	indeterminate
SaProt	LLR -8.30	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -0.48, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,063 bp · p 0.0059 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V162A vs ClinVar V95A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0709% European (non-Finnish) · 837/1,179,776 alleles

Filtering AF 0.0669% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0653%

Overall 0.0569% 919/1,613,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0709%	1,410
Remaining individualsnot grpmax-eligible	0.0624%	1,602
Middle Eastern	0.0495%	2,021
Admixed American	0.025%	4,001
African / African-American	0.0147%	6,823
South Asian	0.00988%	10,120
Finnishnot grpmax-eligible	0.00626%	15,982
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596

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.Val95Ala
Coding: c.284T>C
MANE Select: NM_001042545
dbSNP: rs200888669
Type: single nucleotide variant
Location: chr19:40605068 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53
Residue 162 UniProt numbering: the egf-like 1 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.Val95Met Uncertain significance ★★ ⚠ same residue
LTBP4 p.Gly95Ala Uncertain significance ★ ⚠ same residue
LTBP4 p.Val95= Likely benign ★ 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

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-val95ala (accessed [today's date]).

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