Is TTR p.Pro145Ser (c.433C>T) pathogenic?

TTR p.Pro145Ser (c.433C>T) is classified Uncertain significance in TTR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1408); Very rare (popmax 0.00133%, afr); Associated with amyloidosis, hereditary systemic 1.

What condition is associated with TTR p.Pro145Ser (c.433C>T)?

TTR p.Pro145Ser (c.433C>T) is associated with amyloidosis, hereditary systemic 1 (ClinVar).

How common is TTR p.Pro145Ser (c.433C>T) in the general population?

TTR p.Pro145Ser (c.433C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Hereditary ATTR amyloidosis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TTR p.Pro145Ser (c.433C>T)?

AlphaMissense predicts likely benign (score 0.1408) — an in-silico prediction, not a clinical call.

TTR p.Pro145Ser

c.433C>T · rs1434519437 · VCV2879873

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amyloidosis, hereditary systemic 1

Computational evidence

Protein change
AlphaMissense	0.1408	likely benign
REVEL	0.531	indeterminate
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 6,769 bp · p 0.00021 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 · 1/74,920 alleles

Overall 0.000657% 1/152,184 alleles · very rare

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: TTR
Protein: p.Pro145Ser
Coding: c.433C>T
MANE Select: NM_000371
dbSNP: rs1434519437
Type: single nucleotide variant
Location: chr18:31598664 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI 0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.74 · 493 PDB
Residue 145: an α-helix

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

Disease context

amyloidosis, hereditary systemic 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary ATTR amyloidosis (Orphanet):

Inheritance: Autosomal dominant
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

TTR p.Pro145His Uncertain significance ★★ ⚠ same residue
TTR p.Ala117Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
TTR p.Ala39Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
TTR p.Ala56Pro Pathogenic/Likely pathogenic ★★ same condition
TTR p.Ala65Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
TTR p.Ala65Thr 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-pro145ser (accessed [today's date]).

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