Is TTN p.Pro22355Ser (c.67063C>T) pathogenic?

TTN p.Pro22355Ser (c.67063C>T) is classified Uncertain significance in TTN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.9763); Very rare (popmax 8.48e-05%, nfe); Associated with myopathy, myofibrillar, 9, with early respiratory failure.

What condition is associated with TTN p.Pro22355Ser (c.67063C>T)?

TTN p.Pro22355Ser (c.67063C>T) is associated with myopathy, myofibrillar, 9, with early respiratory failure, tibial muscular dystrophy, dilated cardiomyopathy 1G (ClinVar).

How common is TTN p.Pro22355Ser (c.67063C>T) in the general population?

TTN p.Pro22355Ser (c.67063C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TTN p.Pro22355Ser (c.67063C>T)?

AlphaMissense predicts likely pathogenic (score 0.9763) — an in-silico prediction, not a clinical call.

TTN p.Pro22355Ser

Q: How is Hereditary myopathy with early respiratory failure inherited?

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

c.67063C>T · rs794729481 · VCV202804

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9763 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

myopathy, myofibrillar, 9, with early respiratory failure

Computational evidence

Protein change
AlphaMissense	0.9763	likely pathogenic · top 7% in TTN
REVEL	0.768	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 75 kb · p 3.1e-23 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P20714S vs ClinVar P22355S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,286 alleles

Overall 0.000744% 12/1,612,046 alleles · very rare exomes 10/1,460,006 · genomes 2/152,040 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0271%	3,696
Remaining individualsnot grpmax-eligible	0.00481%	20,787
European (non-Finnish)grpmax	8.48e-05%	1,179,286

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TTN
Protein: p.Pro22355Ser
Coding: c.67063C>T
MANE Select: NM_001267550
dbSNP: rs794729481
Type: single nucleotide variant
Location: chr2:178580224 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)

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

Disease context

myopathy, myofibrillar, 9, with early respiratory failure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tibial muscular dystrophy dilated cardiomyopathy 1G autosomal recessive limb-girdle muscular dystrophy type 2J early-onset myopathy with fatal cardiomyopathy

For Hereditary myopathy with early respiratory failure (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

TTN c.100171+1G>A Likely pathogenic ★★ same condition
TTN c.100766-1G>T Likely pathogenic ★★ same condition
TTN c.100766-2A>T Likely pathogenic ★★ same condition
TTN c.106375-2A>G Pathogenic/Likely pathogenic ★★ same condition
TTN c.106531+1G>A Pathogenic/Likely pathogenic ★★ same condition
TTN c.107224-1G>C Pathogenic/Likely pathogenic ★★ same condition
TTN c.107377+1G>A Pathogenic/Likely pathogenic ★★ same condition
TTN c.107377+1G>C 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/ttn-p-pro22355ser (accessed [today's date]).

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