Is TTN p.Arg19287Cys (c.57859C>T) pathogenic?

TTN p.Arg19287Cys (c.57859C>T) is classified Uncertain significance in TTN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-21). AlphaMissense: likely pathogenic (0.5978); Very rare (popmax 0.00404%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Arg19287Cys (c.57859C>T)?

TTN p.Arg19287Cys (c.57859C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Arg19287Cys (c.57859C>T) in the general population?

TTN p.Arg19287Cys (c.57859C>T) is very rare (popmax 0.00404%, afr) (gnomAD).

What do computational predictors say about TTN p.Arg19287Cys (c.57859C>T)?

AlphaMissense predicts likely pathogenic (score 0.5978) — an in-silico prediction, not a clinical call.

TTN p.Arg19287Cys

c.57859C>T · rs372710684 · VCV518965

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00404%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5978	likely pathogenic
REVEL	0.402	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 75 kb · p 3.1e-23 · regional, not allelic
Overall
CADD	22.9	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 R17646C vs ClinVar R19287C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00404% African / African-American · 3/74,336 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000653%

Overall 0.00118% 19/1,603,564 alleles · very rare exomes 16/1,451,530 · genomes 3/152,034 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00404%	24,779
European (non-Finnish)	0.00136%	73,406

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.Arg19287Cys
Coding: c.57859C>T
MANE Select: NM_001267550
dbSNP: rs372710684
Type: single nucleotide variant
Location: chr2:178594635 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)

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

Similar variants

TTN p.Arg19287His Conflicting classifications of pathogenicity ★ same residue
TTN c.107377+1G>C Pathogenic/Likely pathogenic ★★ same condition
TTN c.54190+1G>A Pathogenic/Likely pathogenic ★★ same condition
TTN c.54811+1G>A Likely pathogenic ★★ same condition
TTN c.57112-1G>A Likely pathogenic ★★ same condition
TTN c.58732+2T>C Likely pathogenic ★★ same condition
TTN c.95723-2A>C Likely pathogenic ★★ same condition
TTN p.Arg1012Ter 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-arg19287cys (accessed [today's date]).

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