Is TTN p.Ser5136= (c.15408G>A) pathogenic?

TTN p.Ser5136= (c.15408G>A) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-25). Very rare (popmax 0.00254%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2J.

What condition is associated with TTN p.Ser5136= (c.15408G>A)?

TTN p.Ser5136= (c.15408G>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2J, tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure (ClinVar).

How common is TTN p.Ser5136= (c.15408G>A) in the general population?

TTN p.Ser5136= (c.15408G>A) is very rare (popmax 0.00254%, nfe) (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.Ser5136=

c.15408G>A · rs761269554 · VCV332933

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -5.2, phastCons 1
Overall
CADD	10.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,704 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00372% 60/1,613,504 alleles · very rare exomes 58/1,461,354 · genomes 2/152,150 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0845%	1,184
Remaining individualsnot grpmax-eligible	0.0048%	20,819
European (non-Finnish)grpmax	0.00254%	39,323
South Asian	0.0022%	45,518

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser5136=
Coding: c.15408G>A
MANE Select: NM_001267550
dbSNP: rs761269554
Type: single nucleotide variant
Location: chr2:178734416 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 5136: the ig-like 32 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: 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-ser5136 (accessed [today's date]).

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