Is LTBP4 p.Arg577Ser (c.1729C>A) pathogenic?

LTBP4 p.Arg577Ser (c.1729C>A) is classified Uncertain significance in LTBP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-12). AlphaMissense: ambiguous (0.4296); Very rare (popmax 8.5e-05%, nfe).

How common is LTBP4 p.Arg577Ser (c.1729C>A) in the general population?

LTBP4 p.Arg577Ser (c.1729C>A) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about LTBP4 p.Arg577Ser (c.1729C>A)?

AlphaMissense predicts ambiguous (score 0.4296) — an in-silico prediction, not a clinical call.

LTBP4 p.Arg577Ser

c.1729C>A · rs1355671197 · VCV2110040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4296	ambiguous
REVEL	0.495	indeterminate
SaProt	LLR -9.83	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 9,612 bp · p 0.91 · regional, not allelic
Overall
CADD	27.4	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 R644S vs ClinVar R577S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,175,844 alleles

Overall 6.28e-05% 1/1,593,144 alleles · very rare exomes 1/1,440,808 · genomes 0/152,336 · 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.Arg577Ser
Coding: c.1729C>A
MANE Select: NM_001042545
dbSNP: rs1355671197
Type: single nucleotide variant
Location: chr19:40610576 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.53
Residue 644 UniProt numbering: the egf-like 5; calcium-binding domain

Full LTBP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LTBP4 c.1307-2A>G Pathogenic/Likely pathogenic ★★ same type
LTBP4 p.Arg677Ter Pathogenic/Likely pathogenic ★★ same type
LTBP4 p.Arg691Ter Pathogenic ★★ same type
LTBP4 c.2944+5G>C Uncertain significance ★★ same type
LTBP4 c.3070+4C>T Uncertain significance ★★ same type
LTBP4 c.*121C>G Uncertain significance ★★ same type
LTBP4 p.Ala1090Thr Uncertain significance ★★ ⚠ same type
LTBP4 p.Ala1125Thr Uncertain significance ★★ ⚠ same type

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-arg577ser (accessed [today's date]).

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