Is TTN p.Val4540= (c.13620G>T) pathogenic?

TTN p.Val4540= (c.13620G>T) is classified Likely benign in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-30). Very rare (popmax 0.00878%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Val4540= (c.13620G>T)?

TTN p.Val4540= (c.13620G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Val4540= (c.13620G>T) in the general population?

TTN p.Val4540= (c.13620G>T) is very rare (popmax 0.00878%, sas) (gnomAD).

TTN p.Val4540=

c.13620G>T · VCV3464260

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP -4.5, phastCons 1
Overall
CADD	0.548	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00878% South Asian · 8/91,078 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00178% 26/1,461,558 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,385
European (non-Finnish)	0.00153%	65,547

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.Val4540=
Coding: c.13620G>T
MANE Select: NM_001267550
Type: single nucleotide variant
Location: chr2:178739613 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 4540: the ig-like 25 domain; a disulfide bond

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.Val4540Met Conflicting classifications of pathogenicity ★ ⚠ same residue
TTN p.His4540Leu Uncertain significance ★ 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-val4540 (accessed [today's date]).

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