Is TTN p.Val20778Phe (c.62332G>T) pathogenic?

TTN p.Val20778Phe (c.62332G>T) is classified Uncertain significance in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-12-28). AlphaMissense: likely benign (0.187); Very rare (popmax 0.00134%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Val20778Phe (c.62332G>T)?

TTN p.Val20778Phe (c.62332G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Val20778Phe (c.62332G>T) in the general population?

TTN p.Val20778Phe (c.62332G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about TTN p.Val20778Phe (c.62332G>T)?

AlphaMissense predicts likely benign (score 0.187) — an in-silico prediction, not a clinical call.

TTN p.Val20778Phe

c.62332G>T · rs754672686 · VCV1732179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.187	likely benign
REVEL	0.276	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 75 kb · p 3.1e-23 · regional, not allelic
Overall
CADD	17.55	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V19137F vs ClinVar V20778F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,872 alleles

Overall 0.000124% 2/1,613,264 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,996
African / African-Americangrpmax	0.00134%	74,872

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val20778Phe
Coding: c.62332G>T
MANE Select: NM_001267550
dbSNP: rs754672686
Type: single nucleotide variant
Location: chr2:178589393 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 20778: the fibronectin type-iii 50 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.Val20778= 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
TTN p.Arg1012Ter Pathogenic/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-val20778phe (accessed [today's date]).

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