Is LTBP2 p.Pro989Arg (c.2966C>G) pathogenic?

LTBP2 p.Pro989Arg (c.2966C>G) is classified Conflicting classifications of pathogenicity in LTBP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0928); Low-frequency (popmax 2.9%, sas); Associated with Weill-Marchesani syndrome.

What condition is associated with LTBP2 p.Pro989Arg (c.2966C>G)?

LTBP2 p.Pro989Arg (c.2966C>G) is associated with Weill-Marchesani syndrome, glaucoma 3, primary congenital, D (ClinVar).

How common is LTBP2 p.Pro989Arg (c.2966C>G) in the general population?

LTBP2 p.Pro989Arg (c.2966C>G) is low-frequency (popmax 2.9%, sas) (gnomAD).

What do computational predictors say about LTBP2 p.Pro989Arg (c.2966C>G)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

LTBP2 p.Pro989Arg

c.2966C>G · rs76172717 · VCV775349

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.9%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Weill-Marchesani syndrome

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.503	indeterminate
SaProt	LLR -6.29	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 107 kb · p 0.013 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.9% South Asian · 2,645/91,084 alleles

Filtering AF 2.81% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.77%

Overall 0.335% 5,403/1,614,156 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.9%	34
Middle Eastern	1.14%	88
Ashkenazi Jewishnot grpmax-eligible	0.419%	239
Remaining individualsnot grpmax-eligible	0.384%	260
Admixed American	0.36%	278
European (non-Finnish)	0.175%	571
African / African-American	0.0413%	2,421
East Asian	0.0134%	7,481
Finnishnot grpmax-eligible	0.00781%	12,797

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: LTBP2
Protein: p.Pro989Arg
Coding: c.2966C>G
MANE Select: NM_000428
dbSNP: rs76172717
Type: single nucleotide variant
Location: chr14:74511307 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 989: the egf-like 7; calcium-binding domain; a disulfide bond

Full LTBP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Weill-Marchesani syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glaucoma 3, primary congenital, D

Similar variants

LTBP2 p.Pro989= Likely benign ★ same residue
LTBP2 c.2389-2A>G Likely pathogenic ★★ same condition
LTBP2 p.Arg299Ter Pathogenic ★★ same condition
LTBP2 p.Cys1438Tyr Likely pathogenic ★★ same condition
LTBP2 c.-55G>A Uncertain significance ★★ same condition
LTBP2 c.-93C>T Uncertain significance ★★ same condition
LTBP2 c.*229C>T Uncertain significance ★★ same condition
LTBP2 p.Ala1359Thr 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/ltbp2-p-pro989arg (accessed [today's date]).

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