Is TTN p.Arg8568= (c.25704G>A) pathogenic?

TTN p.Arg8568= (c.25704G>A) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-06-01). Rare (popmax 0.203%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2J.

How common is TTN p.Arg8568= (c.25704G>A) in the general population?

TTN p.Arg8568= (c.25704G>A) is rare (popmax 0.203%, afr) (gnomAD).

How is Titin-related limb-girdle muscular dystrophy R10 inherited?

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

TTN p.Arg8568=

Q: What condition is associated with TTN p.Arg8568= (c.25704G>A)?

TTN p.Arg8568= (c.25704G>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2J, cardiomyopathy, tibial muscular dystrophy (ClinVar).

c.25704G>A · rs150544093 · VCV46764

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

rare (popmax 0.203%, afr)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2J

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.80	donor loss · deltas
Pangolin	Δ0.22	gain · loss 0.00 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 0.95	GERP -3.5, phastCons 1
Overall
CADD	10.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.203% African / African-American · 152/74,920 alleles

Filtering AF 0.177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.0298% 478/1,605,682 alleles · rare exomes 343/1,453,456 · genomes 135/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.203%	493
Ashkenazi Jewishnot grpmax-eligible	0.16%	625
Middle Eastern	0.116%	864
Admixed American	0.097%	1,031
Remaining individualsnot grpmax-eligible	0.0595%	1,681
European (non-Finnish)	0.0151%	6,604

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.Arg8568=
Coding: c.25704G>A
MANE Select: NM_001267550
dbSNP: rs150544093
Type: single nucleotide variant
Location: chr2:178715710 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 8568: the ig-like 68 domain

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

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2J — 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 early-onset myopathy with fatal cardiomyopathy

For Titin-related limb-girdle muscular dystrophy R10 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

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
TTN c.107377+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-arg8568 (accessed [today's date]).

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