Is LTBP2 p.Pro339Ser (c.1015C>T) pathogenic?

LTBP2 p.Pro339Ser (c.1015C>T) is classified Uncertain significance in LTBP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-30). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.00305%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LTBP2 p.Pro339Ser (c.1015C>T)?

LTBP2 p.Pro339Ser (c.1015C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LTBP2 p.Pro339Ser (c.1015C>T) in the general population?

LTBP2 p.Pro339Ser (c.1015C>T) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about LTBP2 p.Pro339Ser (c.1015C>T)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

LTBP2 p.Pro339Ser

c.1015C>T · rs149632889 · VCV1396260

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.77	GERP -3.7, phastCons 0.81
Regional constraint	o/e 0.94	unconstrained · MANE · 107 kb · p 0.013 · regional, not allelic
Overall
CADD	14.06	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00305% European (non-Finnish) · 36/1,179,752 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00236% 38/1,613,558 alleles · very rare exomes 27/1,461,394 · genomes 11/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00305%	32,771
African / African-American	0.00267%	37,450

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.Pro339Ser
Coding: c.1015C>T
MANE Select: NM_000428
dbSNP: rs149632889
Type: single nucleotide variant
Location: chr14:74555509 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 339: the 'disordered' region

Full LTBP2 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

LTBP3 p.Ala339Thr Uncertain significance ★★ ⚠ same residue
LTBP2 p.Ala1204Thr Uncertain significance ★★ ⚠ same condition
LTBP2 p.Ala1354Val Uncertain significance ★★ same condition
LTBP2 p.Ala1359Val Uncertain significance ★★ same condition
LTBP2 p.Ala141Gly Uncertain significance ★★ ⚠ same condition
LTBP2 p.Ala1421Val Uncertain significance ★★ ⚠ same condition
LTBP2 p.Ala1734Val Uncertain significance ★★ same condition
LTBP2 p.Ala1767Val 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-pro339ser (accessed [today's date]).

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