Is TTN p.Val21458= (c.64374G>A) pathogenic?

TTN p.Val21458= (c.64374G>A) is classified Likely benign in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-24). Very rare (popmax 0.00314%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2J.

How common is TTN p.Val21458= (c.64374G>A) in the general population?

TTN p.Val21458= (c.64374G>A) is very rare (popmax 0.00314%, 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.Val21458=

Q: What condition is associated with TTN p.Val21458= (c.64374G>A)?

TTN p.Val21458= (c.64374G>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2J, dilated cardiomyopathy 1G (ClinVar).

c.64374G>A · rs747623526 · VCV756560

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2J

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.61	GERP -5.7, phastCons 0.013
Overall
CADD	0.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00314% European (non-Finnish) · 37/1,179,336 alleles

Filtering AF 0.00232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00229% 37/1,613,110 alleles · very rare exomes 37/1,460,918 · genomes 0/152,192 · joint denominator

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.Val21458=
Coding: c.64374G>A
MANE Select: NM_001267550
dbSNP: rs747623526
Type: single nucleotide variant
Location: chr2:178586527 (GRCh38)

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: dilated cardiomyopathy 1G

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

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

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-val21458 (accessed [today's date]).

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