Is TTN p.Pro1109Ser (c.3325C>T) pathogenic?

TTN p.Pro1109Ser (c.3325C>T) is classified Uncertain significance in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-01). AlphaMissense: likely pathogenic (0.9821); Very rare (popmax 0.000847%, nfe).

How common is TTN p.Pro1109Ser (c.3325C>T) in the general population?

TTN p.Pro1109Ser (c.3325C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about TTN p.Pro1109Ser (c.3325C>T)?

AlphaMissense predicts likely pathogenic (score 0.9821) — an in-silico prediction, not a clinical call.

TTN p.Pro1109Ser

c.3325C>T · rs375285782 · VCV809106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9821	likely pathogenic · top 6% in TTN
REVEL	0.732	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
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	24.3	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,179,990 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,058 alleles · very rare exomes 10/1,461,834 · genomes 0/152,224 · 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.Pro1109Ser
Coding: c.3325C>T
MANE Select: NM_001267550
dbSNP: rs375285782
Type: single nucleotide variant
Location: chr2:178782267 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 1109: the ig-like 4 domain

Full TTN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TTN p.Pro1109= Likely benign ★★ same residue
TTN c.100171+1G>A Likely pathogenic ★★ same type
TTN c.100766-1G>T Likely pathogenic ★★ same type
TTN c.100766-2A>T Likely pathogenic ★★ same type
TTN c.106375-2A>G Pathogenic/Likely pathogenic ★★ same type
TTN c.106531+1G>A Pathogenic/Likely pathogenic ★★ same type
TTN c.107224-1G>C Pathogenic/Likely pathogenic ★★ same type
TTN c.107377+1G>A Pathogenic/Likely pathogenic ★★ same type

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-pro1109ser (accessed [today's date]).

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