Is TTN p.Arg34709Cys (c.104125C>T) pathogenic?

TTN p.Arg34709Cys (c.104125C>T) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2341); Ultra-rare (popmax 0.012%, afr); Associated with dilated cardiomyopathy 1G.

What condition is associated with TTN p.Arg34709Cys (c.104125C>T)?

TTN p.Arg34709Cys (c.104125C>T) is associated with dilated cardiomyopathy 1G, autosomal recessive limb-girdle muscular dystrophy type 2J, familial hypertrophic cardiomyopathy (ClinVar).

How common is TTN p.Arg34709Cys (c.104125C>T) in the general population?

TTN p.Arg34709Cys (c.104125C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

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

What do computational predictors say about TTN p.Arg34709Cys (c.104125C>T)?

AlphaMissense predicts likely benign (score 0.2341) — an in-silico prediction, not a clinical call.

TTN p.Arg34709Cys

c.104125C>T · rs530959653 · VCV404669

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2341 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

dilated cardiomyopathy 1G

Computational evidence

Protein change
AlphaMissense	0.2341	likely benign
REVEL	0.443	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 75 kb · p 3.1e-23 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R33068C vs ClinVar R34709C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/75,042 alleles

Filtering AF 0.00622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00242% 39/1,613,958 alleles · ultra-rare exomes 30/1,461,684 · genomes 9/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,338
Remaining individualsnot grpmax-eligible	0.008%	12,498
South Asian	0.00769%	13,011
Admixed American	0.00333%	30,008
European (non-Finnish)	0.00136%	73,741

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.Arg34709Cys
Coding: c.104125C>T
MANE Select: NM_001267550
dbSNP: rs530959653
Type: single nucleotide variant
Location: chr2:178532490 (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

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

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2J familial hypertrophic 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.Arg34709His 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-arg34709cys (accessed [today's date]).

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