Is TTR p.Pro22fs (c.65del) pathogenic?

TTR p.Pro22fs (c.65del) is classified Uncertain significance in TTR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-24). No gnomAD frequency available for this variant; Associated with amyloidosis, hereditary systemic 1.

What condition is associated with TTR p.Pro22fs (c.65del)?

TTR p.Pro22fs (c.65del) is associated with amyloidosis, hereditary systemic 1 (ClinVar).

How common is TTR p.Pro22fs (c.65del) in the general population?

TTR p.Pro22fs (c.65del) is no gnomAD frequency available for this variant (gnomAD).

How is Hereditary ATTR amyloidosis inherited?

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

TTR p.Pro22fs

c.65del · rs2510932013 · VCV2119686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

amyloidosis, hereditary systemic 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.94	GERP -3.4, phastCons 0.029

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TTR
Protein: p.Pro22fs
Coding: c.65del
MANE Select: NM_000371
dbSNP: rs2510932013
Type: Deletion
Location: chr18:31591965 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI 0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.74 · 493 PDB

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.Pro22Leu Uncertain significance ★★ ⚠ same residue
TTR p.Pro22= Likely benign ★★ same residue
TTR p.His4del Uncertain significance ★★ same condition
TTR p.Leu78fs Uncertain significance ★★ same condition
TTR c.337-527_349del Uncertain significance ★ same condition
TTR c.69+4_69+7del Uncertain significance ★ same condition
TTR c.70-20del Uncertain significance ★ same condition
TTR p.Glu81_Phe84del Conflicting classifications of pathogenicity ★ 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-pro22fs (accessed [today's date]).

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