Is TTN p.Val22017= (c.66051G>A) pathogenic?

TTN p.Val22017= (c.66051G>A) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-24). Rare (popmax 0.132%, mid); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Val22017= (c.66051G>A)?

TTN p.Val22017= (c.66051G>A) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy 1G (ClinVar).

How common is TTN p.Val22017= (c.66051G>A) in the general population?

TTN p.Val22017= (c.66051G>A) is rare (popmax 0.132%, mid) (gnomAD).

TTN p.Val22017=

c.66051G>A · rs587780981 · VCV137801

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Conditions

Cardiovascular phenotype

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 1.5	GERP -0.73, phastCons 1
Overall
CADD	1.162	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,052 alleles

Filtering AF 0.0657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.048%

Overall 0.0107% 173/1,612,868 alleles · rare exomes 157/1,460,732 · genomes 16/152,136 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	756
Ashkenazi Jewishnot grpmax-eligible	0.0879%	1,138
Admixed American	0.0667%	1,499
Remaining individualsnot grpmax-eligible	0.0384%	2,601
European (non-Finnish)	0.00611%	16,380
African / African-American	0.004%	24,997

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.Val22017=
Coding: c.66051G>A
MANE Select: NM_001267550
dbSNP: rs587780981
Type: single nucleotide variant
Location: chr2:178582405 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 22017: the ig-like 115 domain

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: cardiomyopathy dilated cardiomyopathy 1G autosomal recessive limb-girdle muscular dystrophy type 2J

Similar variants

TTN p.Val22017Met 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-val22017 (accessed [today's date]).

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