Is TTN p.Tyr4287Cys (c.12860A>G) pathogenic?

TTN p.Tyr4287Cys (c.12860A>G) is classified Uncertain significance in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-27). AlphaMissense: likely benign (0.0694); Rare (popmax 0.243%, eas); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Tyr4287Cys (c.12860A>G)?

TTN p.Tyr4287Cys (c.12860A>G) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Tyr4287Cys (c.12860A>G) in the general population?

TTN p.Tyr4287Cys (c.12860A>G) is rare (popmax 0.243%, eas) (gnomAD).

What do computational predictors say about TTN p.Tyr4287Cys (c.12860A>G)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

TTN p.Tyr4287Cys

c.12860A>G · rs183493501 · VCV1740934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.243%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP -4
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	13.52	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Y3970C vs ClinVar Y4287C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.243% East Asian · 109/44,798 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.192%

Overall 0.00725% 117/1,613,594 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.243%	411
African / African-American	0.00133%	75,038
European (non-Finnish)	0.000593%	168,534

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.Tyr4287Cys
Coding: c.12860A>G
MANE Select: NM_001267550
dbSNP: rs183493501
Type: single nucleotide variant
Location: chr2:178740373 (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.Tyr4287= Likely benign ★ 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-tyr4287cys (accessed [today's date]).

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