Is TTN p.Pro4039= (c.12117C>T) pathogenic?

TTN p.Pro4039= (c.12117C>T) is classified Benign in TTN (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-03). Common (popmax 7.05%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Pro4039= (c.12117C>T)?

TTN p.Pro4039= (c.12117C>T) is associated with Cardiovascular phenotype, cardiomyopathy, tibial muscular dystrophy (ClinVar).

TTN p.Pro4039=

Q: How common is TTN p.Pro4039= (c.12117C>T) in the general population?

TTN p.Pro4039= (c.12117C>T) is common (popmax 7.05%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.12117C>T · rs55895721 · VCV47816

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 7.05%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

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 0.061	GERP -2.4, phastCons 0.001
Overall
CADD	1.179	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.05% African / African-American · 5,289/75,018 alleles

Filtering AF 6.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.83%

Overall 0.372% 6,010/1,613,698 alleles · common exomes 3,023/1,461,436 · genomes 2,987/152,262 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.05%	14
Middle Eastern	0.545%	184
Remaining individualsnot grpmax-eligible	0.523%	191
Admixed American	0.35%	286
South Asian	0.022%	4,554
European (non-Finnish)	0.0111%	9,006

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.Pro4039=
Coding: c.12117C>T
MANE Select: NM_001267550
dbSNP: rs55895721
Type: single nucleotide variant
Location: chr2:178741116 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

TTN p.His4039Leu Uncertain significance ★ same residue
TTN p.Pro4039Leu Uncertain significance ★ ⚠ 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

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-pro4039 (accessed [today's date]).

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