Is TTN p.Leu35626Val (c.106876T>G) pathogenic?

TTN p.Leu35626Val (c.106876T>G) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-10-10). AlphaMissense: likely benign (0.2341); Ultra-rare (popmax 0.0546%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Leu35626Val (c.106876T>G)?

TTN p.Leu35626Val (c.106876T>G) is associated with Cardiovascular phenotype, tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure (ClinVar).

How common is TTN p.Leu35626Val (c.106876T>G) in the general population?

TTN p.Leu35626Val (c.106876T>G) is ultra-rare (popmax 0.0546%, afr) (gnomAD).

What do computational predictors say about TTN p.Leu35626Val (c.106876T>G)?

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

TTN p.Leu35626Val

c.106876T>G · rs373152640 · VCV178152

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2341 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0546%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2341	likely benign
REVEL	0.457	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.12	GERP -5.4, phastCons 0.019
Regional constraint	o/e 0.93	unconstrained · MANE · 75 kb · p 3.1e-23 · regional, not allelic
Overall
CADD	4.519	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 L33985V vs ClinVar L35626V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0546% African / African-American · 41/75,052 alleles

Filtering AF 0.0413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.0044% 71/1,613,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0546%	1,831
Remaining individualsnot grpmax-eligible	0.0208%	4,806
East Asian	0.0178%	5,611
Middle Eastern	0.0165%	6,062
South Asian	0.00329%	30,361
European (non-Finnish)	0.000424%	235,977

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.Leu35626Val
Coding: c.106876T>G
dbSNP: rs373152640
Type: single nucleotide variant
Location: chr2:178528875 (GRCh38)

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

Disease context

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

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-leu35626val (accessed [today's date]).

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