Is TTN p.Pro862Ser (c.2584C>T) pathogenic?

TTN p.Pro862Ser (c.2584C>T) is classified Uncertain significance in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-27). AlphaMissense: likely benign (0.2787); Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Pro862Ser (c.2584C>T)?

TTN p.Pro862Ser (c.2584C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Pro862Ser (c.2584C>T) in the general population?

TTN p.Pro862Ser (c.2584C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TTN p.Pro862Ser (c.2584C>T)?

AlphaMissense predicts likely benign (score 0.2787) — an in-silico prediction, not a clinical call.

TTN p.Pro862Ser

c.2584C>T · rs1393348431 · VCV1791396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2787	likely benign
REVEL	0.354	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,002 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,982 alleles · very rare exomes 1/1,461,816 · genomes 1/152,166 · joint denominator

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.Pro862Ser
Coding: c.2584C>T
MANE Select: NM_001267550
dbSNP: rs1393348431
Type: single nucleotide variant
Location: chr2:178784261 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 862: the 'disordered' region

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.Pro862Leu Uncertain significance ★ same residue
TTN p.Pro862= 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

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-pro862ser (accessed [today's date]).

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