Is LTBP2 p.Ser1548Phe (c.4643C>T) pathogenic?

LTBP2 p.Ser1548Phe (c.4643C>T) is classified Uncertain significance in LTBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: ambiguous (0.419); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with LTBP2 p.Ser1548Phe (c.4643C>T)?

LTBP2 p.Ser1548Phe (c.4643C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LTBP2 p.Ser1548Phe (c.4643C>T) in the general population?

LTBP2 p.Ser1548Phe (c.4643C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about LTBP2 p.Ser1548Phe (c.4643C>T)?

AlphaMissense predicts ambiguous (score 0.419) — an in-silico prediction, not a clinical call.

LTBP2 p.Ser1548Phe

c.4643C>T · VCV3868961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.419 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.419	ambiguous
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -11.94	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 3,963 bp · p 0.0091 · regional, not allelic
Overall
CADD	32.0	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 0.00133% African / African-American · 1/74,944 alleles

Overall 6.2e-05% 1/1,613,744 alleles · very rare exomes 0/1,461,484 · genomes 1/152,260 · 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: LTBP2
Protein: p.Ser1548Phe
Coding: c.4643C>T
MANE Select: NM_000428
Type: single nucleotide variant
Location: chr14:74503546 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.33
Residue 1548: the egf-like 18; calcium-binding domain

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

LTBP2 p.Ser1548Pro 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-ser1548phe (accessed [today's date]).

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