Is LTBP4 p.Ser233Phe (c.698C>T) pathogenic?

LTBP4 p.Ser233Phe (c.698C>T) is classified Uncertain significance in LTBP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-21). AlphaMissense: likely benign (0.1867); Ultra-rare (popmax 0.0195%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LTBP4 p.Ser233Phe (c.698C>T)?

LTBP4 p.Ser233Phe (c.698C>T) is associated with Inborn genetic diseases, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (ClinVar).

How common is LTBP4 p.Ser233Phe (c.698C>T) in the general population?

LTBP4 p.Ser233Phe (c.698C>T) is ultra-rare (popmax 0.0195%, nfe) (gnomAD).

What do computational predictors say about LTBP4 p.Ser233Phe (c.698C>T)?

AlphaMissense predicts likely benign (score 0.1867) — an in-silico prediction, not a clinical call.

LTBP4 p.Ser233Phe

c.698C>T · rs886054445 · VCV329304

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0195%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1867	likely benign
REVEL	0.769	pathogenic-leaning
SaProt	LLR -5.08	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 0.56, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,063 bp · p 0.0059 · regional, not allelic
Overall
CADD	27.1	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 S300F vs ClinVar S233F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0195% European (non-Finnish) · 224/1,146,520 alleles

Filtering AF 0.0174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.0149% 231/1,545,678 alleles · ultra-rare exomes 221/1,393,448 · genomes 10/152,230 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0195%	5,118
Remaining individualsnot grpmax-eligible	0.01%	9,992
African / African-American	0.00137%	73,002

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.Ser233Phe
Coding: c.698C>T
MANE Select: NM_001042545
dbSNP: rs886054445
Type: single nucleotide variant
Location: chr19:40605736 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53
Residue 300 UniProt numbering: the tb 1 domain

Full LTBP4 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

Also linked: cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

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.Ala182Thr Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala207Val 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-ser233phe (accessed [today's date]).

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