Is TTN p.Ser8958Pro (c.26872T>C) pathogenic?

TTN p.Ser8958Pro (c.26872T>C) is classified Uncertain significance in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2013-10-18). AlphaMissense: likely pathogenic (0.9106); Very rare (popmax 8.48e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Ser8958Pro (c.26872T>C)?

TTN p.Ser8958Pro (c.26872T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Ser8958Pro (c.26872T>C) in the general population?

TTN p.Ser8958Pro (c.26872T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TTN p.Ser8958Pro (c.26872T>C)?

AlphaMissense predicts likely pathogenic (score 0.9106) — an in-silico prediction, not a clinical call.

TTN p.Ser8958Pro

c.26872T>C · rs886038913 · VCV263748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9106	likely pathogenic
REVEL	0.567	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	19.52	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 S8641P vs ClinVar S8958P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,042 alleles

Overall 0.000657% 1/152,142 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.Ser8958Pro
Coding: c.26872T>C
MANE Select: NM_001267550
dbSNP: rs886038913
Type: single nucleotide variant
Location: chr2:178713262 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 8958: a disulfide bond; the ig-like 72 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.Ser8958Phe Uncertain significance ★ ⚠ same residue
TTN p.Ser8958= 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-ser8958pro (accessed [today's date]).

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