Is TTN p.Ala69= (c.207C>T) pathogenic?

TTN p.Ala69= (c.207C>T) is classified Likely benign in TTN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-18). Ultra-rare (popmax 0.028%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2J.

How common is TTN p.Ala69= (c.207C>T) in the general population?

TTN p.Ala69= (c.207C>T) is ultra-rare (popmax 0.028%, 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.Ala69=

Q: What condition is associated with TTN p.Ala69= (c.207C>T)?

TTN p.Ala69= (c.207C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2J, cardiomyopathy, dilated cardiomyopathy 1G (ClinVar).

c.207C>T · rs150548328 · VCV466884

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2J

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 2, phastCons 1
Overall
CADD	16.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/75,038 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00279% 45/1,614,118 alleles · ultra-rare exomes 31/1,461,832 · genomes 14/152,286 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,573
East Asian	0.0134%	7,480
South Asian	0.00878%	11,385
Admixed American	0.005%	20,007
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000508%	196,662

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.Ala69=
Coding: c.207C>T
MANE Select: NM_001267550
dbSNP: rs150548328
Type: single nucleotide variant
Location: chr2:178802226 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 69: the ig-like 1 domain; a β-strand

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 dilated cardiomyopathy 1G

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

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

TTN p.Ala69Thr 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
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-ala69 (accessed [today's date]).

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