Is LTBP4 p.Pro970Arg (c.2909C>G) pathogenic?

LTBP4 p.Pro970Arg (c.2909C>G) is classified Conflicting classifications of pathogenicity in LTBP4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1263); Rare (popmax 0.284%, afr); Associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies.

What condition is associated with LTBP4 p.Pro970Arg (c.2909C>G)?

LTBP4 p.Pro970Arg (c.2909C>G) is associated with cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (ClinVar).

How common is LTBP4 p.Pro970Arg (c.2909C>G) in the general population?

LTBP4 p.Pro970Arg (c.2909C>G) is rare (popmax 0.284%, afr) (gnomAD).

What do computational predictors say about LTBP4 p.Pro970Arg (c.2909C>G)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

LTBP4 p.Pro970Arg

c.2909C>G · rs200667255 · VCV329322

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.284%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Computational evidence

Protein change
AlphaMissense	0.1263	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 9,612 bp · p 0.91 · regional, not allelic
Overall
CADD	25.0	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 P1037R vs ClinVar P970R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.284% African / African-American · 213/75,072 alleles

Filtering AF 0.252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.24%

Overall 0.0788% 1,272/1,613,978 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.17%	46
African / African-Americangrpmax	0.284%	352
Middle Eastern	0.231%	433
Remaining individualsnot grpmax-eligible	0.206%	484
Admixed American	0.0483%	2,070
European (non-Finnish)	0.019%	5,267
South Asian	0.0143%	7,005
Finnishnot grpmax-eligible	0.0125%	8,004

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro970Arg
Coding: c.2909C>G
MANE Select: NM_001042545
dbSNP: rs200667255
Type: single nucleotide variant
Location: chr19:40616985 (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-pro970arg (accessed [today's date]).

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