Is LTBP4 p.Ser676Phe (c.2027C>T) pathogenic?

LTBP4 p.Ser676Phe (c.2027C>T) is classified Uncertain significance in LTBP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: ambiguous (0.5092); Very rare (popmax 0.00402%, afr); Associated with Inborn genetic diseases.

What condition is associated with LTBP4 p.Ser676Phe (c.2027C>T)?

LTBP4 p.Ser676Phe (c.2027C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LTBP4 p.Ser676Phe (c.2027C>T) in the general population?

LTBP4 p.Ser676Phe (c.2027C>T) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about LTBP4 p.Ser676Phe (c.2027C>T)?

AlphaMissense predicts ambiguous (score 0.5092) — an in-silico prediction, not a clinical call.

LTBP4 p.Ser676Phe

c.2027C>T · VCV4049911

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5092	ambiguous
REVEL	0.496	indeterminate
SaProt	LLR -9.19	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 9,612 bp · p 0.91 · regional, not allelic
Overall
CADD	23.7	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 S743F vs ClinVar S676F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00402% African / African-American · 3/74,710 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000187% 3/1,608,106 alleles · very rare exomes 1/1,456,258 · genomes 2/151,848 · 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: LTBP4
Protein: p.Ser676Phe
Coding: c.2027C>T
MANE Select: NM_001042545
Type: single nucleotide variant
Location: chr19:40611368 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53
Residue 743 UniProt numbering: the egf-like 7; calcium-binding 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

Similar variants

LTBP4 p.Ala182Thr Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala207Val Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala23Val Uncertain significance ★★ same condition
LTBP4 p.Ala775Val Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala796Gly Uncertain significance ★★ ⚠ same condition
LTBP4 p.Ala967Pro Uncertain significance ★★ ⚠ same condition
LTBP4 p.Arg102Gly Uncertain significance ★★ ⚠ same condition
LTBP4 p.Arg193Leu 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-ser676phe (accessed [today's date]).

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