Is TTN p.Phe229= (c.687T>C) pathogenic?

TTN p.Phe229= (c.687T>C) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0325%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Phe229= (c.687T>C)?

TTN p.Phe229= (c.687T>C) is associated with Cardiovascular phenotype, tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure (ClinVar).

How common is TTN p.Phe229= (c.687T>C) in the general population?

TTN p.Phe229= (c.687T>C) is ultra-rare (popmax 0.0325%, nfe) (gnomAD).

TTN p.Phe229=

c.687T>C · rs376527094 · VCV178277

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0325%, nfe)

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 9.4	GERP 1, phastCons 1
Overall
CADD	13.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0325% European (non-Finnish) · 383/1,180,032 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0287%

Overall 0.026% 419/1,614,210 alleles · ultra-rare exomes 393/1,461,848 · genomes 26/152,362 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0325%	3,081
Admixed American	0.03%	3,335
Remaining individualsnot grpmax-eligible	0.0192%	5,209
African / African-American	0.00666%	15,012
South Asian	0.0011%	91,088

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.Phe229=
Coding: c.687T>C
MANE Select: NM_001267550
dbSNP: rs376527094
Type: single nucleotide variant
Location: chr2:178799714 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 229: a β-strand

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

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-phe229 (accessed [today's date]).

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