Is LTBP2 p.Glu1237Lys (c.3709G>A) pathogenic?

LTBP2 p.Glu1237Lys (c.3709G>A) is classified Uncertain significance in LTBP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-10). AlphaMissense: likely benign (0.085); Ultra-rare (popmax 0.0165%, mid); Associated with Weill-Marchesani syndrome.

What condition is associated with LTBP2 p.Glu1237Lys (c.3709G>A)?

LTBP2 p.Glu1237Lys (c.3709G>A) is associated with Weill-Marchesani syndrome, glaucoma 3, primary congenital, D (ClinVar).

How common is LTBP2 p.Glu1237Lys (c.3709G>A) in the general population?

LTBP2 p.Glu1237Lys (c.3709G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about LTBP2 p.Glu1237Lys (c.3709G>A)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

LTBP2 p.Glu1237Lys

c.3709G>A · rs769155905 · VCV884668

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Weill-Marchesani syndrome

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.475	indeterminate
SaProt	LLR -10.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 107 kb · p 0.013 · regional, not allelic
Overall
CADD	28.1	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 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00378% 61/1,613,870 alleles · ultra-rare exomes 54/1,461,630 · genomes 7/152,240 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Middle Easterngrpmax	0.0165%	6,076
African / African-American	0.004%	24,981
European (non-Finnish)	0.0039%	25,653
Remaining individualsnot grpmax-eligible	0.0032%	31,240
South Asian	0.0022%	45,544

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: LTBP2
Protein: p.Glu1237Lys
Coding: c.3709G>A
MANE Select: NM_000428
dbSNP: rs769155905
Type: single nucleotide variant
Location: chr14:74508039 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 1237: the egf-like 13; calcium-binding domain

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 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
LTBP2 p.Ala733Thr 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-glu1237lys (accessed [today's date]).

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