Is TTN p.Pro5277= (c.15831C>T) pathogenic?

TTN p.Pro5277= (c.15831C>T) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-05). Ultra-rare (popmax 0.0329%, mid); Associated with early-onset myopathy with fatal cardiomyopathy.

What condition is associated with TTN p.Pro5277= (c.15831C>T)?

TTN p.Pro5277= (c.15831C>T) is associated with early-onset myopathy with fatal cardiomyopathy, tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure (ClinVar).

How common is TTN p.Pro5277= (c.15831C>T) in the general population?

TTN p.Pro5277= (c.15831C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Early-onset myopathy with fatal cardiomyopathy inherited?

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

TTN p.Pro5277=

c.15831C>T · rs780784090 · VCV332931

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

early-onset myopathy with fatal cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.016	GERP -4.9, phastCons 0.94
Overall
CADD	2.108	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00167% 27/1,613,592 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
Admixed American	0.01%	9,999
Remaining individualsnot grpmax-eligible	0.0064%	15,616
African / African-American	0.00267%	37,453
Finnishnot grpmax-eligible	0.00156%	63,972
European (non-Finnish)	0.00102%	98,312

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.Pro5277=
Coding: c.15831C>T
MANE Select: NM_001267550
dbSNP: rs780784090
Type: single nucleotide variant
Location: chr2:178733462 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 5277: the ig-like 33 domain; a disulfide bond

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

Disease context

early-onset myopathy with fatal cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tibial muscular dystrophy myopathy, myofibrillar, 9, with early respiratory failure dilated cardiomyopathy 1G autosomal recessive limb-girdle muscular dystrophy type 2J

For Early-onset myopathy with fatal cardiomyopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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-pro5277 (accessed [today's date]).

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