Is TTN p.Pro4289= (c.12867C>T) pathogenic?

TTN p.Pro4289= (c.12867C>T) is classified Likely benign in TTN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-12). Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Pro4289= (c.12867C>T)?

TTN p.Pro4289= (c.12867C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1G, autosomal recessive limb-girdle muscular dystrophy type 2J (ClinVar).

How common is TTN p.Pro4289= (c.12867C>T) in the general population?

TTN p.Pro4289= (c.12867C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

TTN p.Pro4289=

c.12867C>T · rs768686613 · VCV2153059

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 0.11	GERP -2.2, phastCons 0.89
Overall
CADD	4.243	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,058 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,416 alleles · very rare exomes 5/1,461,314 · genomes 3/152,102 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,058
European (non-Finnish)	0.000593%	168,536

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.Pro4289=
Coding: c.12867C>T
MANE Select: NM_001267550
dbSNP: rs768686613
Type: single nucleotide variant
Location: chr2:178740366 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 4289: the ig-like 23 domain

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: dilated cardiomyopathy 1G autosomal recessive limb-girdle muscular dystrophy type 2J

Similar variants

TTN p.Pro4289_Leu4290insTer Likely pathogenic ★ 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-pro4289 (accessed [today's date]).

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