Is TTN p.Pro6Ser (c.16C>T) pathogenic?

TTN p.Pro6Ser (c.16C>T) is classified Uncertain significance in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-15). AlphaMissense: likely pathogenic (0.9522); No allele count reported in gnomAD v4.1 (AN 1,613,906).

How common is TTN p.Pro6Ser (c.16C>T) in the general population?

TTN p.Pro6Ser (c.16C>T) is no allele count reported in gnomAD v4.1 (AN 1,613,906) (gnomAD).

What do computational predictors say about TTN p.Pro6Ser (c.16C>T)?

AlphaMissense predicts likely pathogenic (score 0.9522) — an in-silico prediction, not a clinical call.

TTN p.Pro6Ser

c.16C>T · VCV3573730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9522 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,906)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9522	likely pathogenic · top 10% in TTN
REVEL	0.726	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	25.6	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

No allele count reported in gnomAD v4.1 (AN 1,613,906). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TTN
Protein: p.Pro6Ser
Coding: c.16C>T
MANE Select: NM_001267550
Type: single nucleotide variant
Location: chr2:178804627 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 6: the ig-like 1 domain; a β-strand

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

Similar variants

TTN p.Pro6= Likely benign ★★ same residue
TTN p.Pro6Leu Conflicting classifications of pathogenicity ★ 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

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-pro6ser (accessed [today's date]).

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