Is TTN p.Leu28964Pro (c.86891T>C) pathogenic?

TTN p.Leu28964Pro (c.86891T>C) is classified Uncertain significance in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-18). AlphaMissense: ambiguous (0.3836); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Leu28964Pro (c.86891T>C)?

TTN p.Leu28964Pro (c.86891T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Leu28964Pro (c.86891T>C) in the general population?

TTN p.Leu28964Pro (c.86891T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TTN p.Leu28964Pro (c.86891T>C)?

AlphaMissense predicts ambiguous (score 0.3836) — an in-silico prediction, not a clinical call.

TTN p.Leu28964Pro

c.86891T>C · rs781089608 · VCV1750763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3836	ambiguous
REVEL	0.294	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 75 kb · p 3.1e-23 · regional, not allelic
Overall
CADD	17.62	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L27323P vs ClinVar L28964P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,020 alleles

Overall 6.84e-05% 1/1,461,476 alleles · very rare

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.Leu28964Pro
Coding: c.86891T>C
MANE Select: NM_001267550
dbSNP: rs781089608
Type: single nucleotide variant
Location: chr2:178558568 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 28964: the ig-like 133 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

Similar variants

TTN p.Leu28964= 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-leu28964pro (accessed [today's date]).

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