Is TTN p.Pro12977Ser (c.38929C>T) pathogenic?

TTN p.Pro12977Ser (c.38929C>T) is classified Benign/Likely benign in TTN (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.31%, sas); Associated with dilated cardiomyopathy 1G.

What condition is associated with TTN p.Pro12977Ser (c.38929C>T)?

TTN p.Pro12977Ser (c.38929C>T) is associated with dilated cardiomyopathy 1G, tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure (ClinVar).

How common is TTN p.Pro12977Ser (c.38929C>T) in the general population?

TTN p.Pro12977Ser (c.38929C>T) is low-frequency (popmax 2.31%, sas) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

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

TTN p.Pro12977Ser

c.38929C>T · rs150223722 · VCV238766

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.31%, sas)

Conditions

dilated cardiomyopathy 1G

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 1.7	GERP -2, phastCons 0.009
Regional constraint	o/e 1.14	unconstrained · MANE · 14 kb · p 5e-05 · regional, not allelic
Overall
CADD	15.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.31% South Asian · 2,093/90,722 alleles

Filtering AF 2.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.19%

Overall 0.616% 9,925/1,611,716 alleles · low-frequency exomes 9,324/1,459,556 · genomes 601/152,160 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.31%	43
Middle Eastern	1.03%	97
European (non-Finnish)	0.604%	166
Remaining individualsnot grpmax-eligible	0.562%	178
Admixed American	0.208%	481
Finnishnot grpmax-eligible	0.138%	726
African / African-American	0.1%	997
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,212
East Asian	0.00446%	22,409

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.Pro12977Ser
Coding: c.38929C>T
MANE Select: NM_001267550
dbSNP: rs150223722
Type: single nucleotide variant
Location: chr2:178652878 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 12977: the ig-like 86 domain

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

Disease context

dilated cardiomyopathy 1G — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

TTN p.Pro12977= Likely benign ★★ same residue
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

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-pro12977ser (accessed [today's date]).

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