Is LTBP4 p.Asp643Val (c.1928A>T) pathogenic?

LTBP4 p.Asp643Val (c.1928A>T) is classified Uncertain significance in LTBP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-29). AlphaMissense: likely pathogenic (0.9483); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with LTBP4 p.Asp643Val (c.1928A>T)?

LTBP4 p.Asp643Val (c.1928A>T) is associated with Inborn genetic diseases (ClinVar).

How common is LTBP4 p.Asp643Val (c.1928A>T) in the general population?

LTBP4 p.Asp643Val (c.1928A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about LTBP4 p.Asp643Val (c.1928A>T)?

AlphaMissense predicts likely pathogenic (score 0.9483) — an in-silico prediction, not a clinical call.

LTBP4 p.Asp643Val

c.1928A>T · rs2515360486 · VCV2258304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9483 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9483	likely pathogenic
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -15.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 9,612 bp · p 0.91 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 D710V vs ClinVar D643V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,750 alleles

Overall 6.2e-05% 1/1,612,310 alleles · very rare exomes 1/1,460,370 · genomes 0/151,940 · joint denominator

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.Asp643Val
Coding: c.1928A>T
MANE Select: NM_001042545
dbSNP: rs2515360486
Type: single nucleotide variant
Location: chr19:40611269 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53
Residue 710 UniProt numbering: the egf-like 7; calcium-binding domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LTBP4 p.Asp643Tyr Uncertain significance ★ ⚠ same residue
LTBP4 p.Ala182Thr Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala207Val Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala23Val Uncertain significance ★★ same condition
LTBP4 p.Ala775Val Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala796Gly Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala967Pro Uncertain significance ★★ ⚠ same condition
LTBP4 p.Arg102Gly 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-asp643val (accessed [today's date]).

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