TTR p.Arg124Pro
c.371G>C · VCV4193820
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely pathogenic
0.6082 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
1/2 damaging
AlphaMissense, SaProt · REVEL indeterminate
Conditions
1
Cardiovascular phenotype
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6082 | likely pathogenic |
|---|---|---|
| REVEL | 0.639 | indeterminate |
| SaProt | LLR -9.62 | tolerated |
| ⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 0.65 | GERP -4.2 |
| Regional constraint | o/e 0.73 | unconstrained · MANE · 6,769 bp · p 0.00021 · regional, not allelic |
| Overall | ||
| CADD | 15.44 | 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
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- TTR
- Protein
- p.Arg124Pro
- Coding
- c.371G>C
- MANE Select
- NM_000371
- Type
- single nucleotide variant
- Location
- chr18:31598602 (GRCh38)
- Gene constraint
- LOEUF 1.049 · pLI 0.01 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 88.74 · 493 PDB
- Residue 124
- a β-strand; a UniProt-annotated variant site (in)
Similar variants
- TTR p.Arg124Cys Uncertain significance ★★ ⚠ same residue
- TTR p.Arg124= Benign/Likely benign ★★ same residue
- TTR p.Arg124His Conflicting classifications of pathogenicity ★ ⚠ same residue
- TTR p.Arg124Leu Uncertain significance ★ ⚠ same residue
- TTR p.Ala39Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
- TTR p.Ala56Pro Pathogenic/Likely pathogenic ★★ same condition
- TTR p.Ala65Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
- TTR p.Arg54Thr Pathogenic/Likely pathogenic ★★ 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/ttr-p-arg124pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown