Is TTN p.Pro4108= (c.12324T>C) pathogenic?

TTN p.Pro4108= (c.12324T>C) is classified Likely benign in TTN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-10). Ultra-rare (popmax 0.0379%, eas); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Pro4108= (c.12324T>C)?

TTN p.Pro4108= (c.12324T>C) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy 1G (ClinVar).

How common is TTN p.Pro4108= (c.12324T>C) in the general population?

TTN p.Pro4108= (c.12324T>C) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

TTN p.Pro4108=

c.12324T>C · rs537284713 · VCV413205

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

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 0.3	GERP -5.1
Overall
CADD	0.735	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0379% East Asian · 17/44,854 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00149% 24/1,613,928 alleles · ultra-rare exomes 20/1,461,584 · genomes 4/152,344 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,638
African / African-American	0.00933%	10,723

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.Pro4108=
Coding: c.12324T>C
MANE Select: NM_001267550
dbSNP: rs537284713
Type: single nucleotide variant
Location: chr2:178740909 (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 dilated cardiomyopathy 1G autosomal recessive limb-girdle muscular dystrophy type 2J

Similar variants

TTN p.Pro4108fs Conflicting classifications of pathogenicity ★ 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-pro4108 (accessed [today's date]).

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