Is TTN p.Ser8065Pro (c.24193T>C) pathogenic?

TTN p.Ser8065Pro (c.24193T>C) is classified Likely benign in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.7379); Very rare (popmax 0.00133%, afr).

How common is TTN p.Ser8065Pro (c.24193T>C) in the general population?

TTN p.Ser8065Pro (c.24193T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TTN p.Ser8065Pro (c.24193T>C)?

AlphaMissense predicts likely pathogenic (score 0.7379) — an in-silico prediction, not a clinical call.

TTN p.Ser8065Pro

c.24193T>C · VCV4684619

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7379 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.7379	likely pathogenic
REVEL	0.273	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S7748P vs ClinVar S8065P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,018 alleles

Overall 6.2e-05% 1/1,613,698 alleles · very rare exomes 1/1,461,470 · genomes 0/152,228 · 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.Ser8065Pro
Coding: c.24193T>C
MANE Select: NM_001267550
Type: single nucleotide variant
Location: chr2:178719197 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)

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

Similar variants

TTN p.Ser8065= Benign/Likely benign ★★ same residue
TTN p.Ser8065Cys Uncertain significance ★ 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-ser8065pro (accessed [today's date]).

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