Is TTN p.Pro3990Leu (c.11969C>T) pathogenic?

TTN p.Pro3990Leu (c.11969C>T) is classified Benign/Likely benign in TTN (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1382); Low-frequency (popmax 1.26%, nfe); Associated with Supraventricular tachycardia.

What condition is associated with TTN p.Pro3990Leu (c.11969C>T)?

TTN p.Pro3990Leu (c.11969C>T) is associated with Supraventricular tachycardia, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

How common is TTN p.Pro3990Leu (c.11969C>T) in the general population?

TTN p.Pro3990Leu (c.11969C>T) is low-frequency (popmax 1.26%, nfe) (gnomAD).

What do computational predictors say about TTN p.Pro3990Leu (c.11969C>T)?

AlphaMissense predicts likely benign (score 0.1382) — an in-silico prediction, not a clinical call.

TTN p.Pro3990Leu

c.11969C>T · rs33971253 · VCV47814

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.1382 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.26%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Supraventricular tachycardia

Computational evidence

Protein change
AlphaMissense	0.1382	likely benign
REVEL	0.236	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	20.8	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 P3673L vs ClinVar P3990L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.26% European (non-Finnish) · 14,904/1,179,834 alleles

Filtering AF 1.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.24%

Overall 1% 16,197/1,613,806 alleles · low-frequency exomes 15,223/1,461,518 · genomes 974/152,288 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.26%	79
Remaining individualsnot grpmax-eligible	0.856%	117
Ashkenazi Jewishnot grpmax-eligible	0.402%	249
Finnishnot grpmax-eligible	0.366%	273
Admixed American	0.298%	335
African / African-American	0.229%	436
South Asian	0.056%	1,786
Middle Eastern	0.0495%	2,021

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.Pro3990Leu
Coding: c.11969C>T
MANE Select: NM_001267550
dbSNP: rs33971253
Type: single nucleotide variant
Location: chr2:178741264 (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

Disease context

Supraventricular tachycardia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy hypertrophic cardiomyopathy tibial muscular dystrophy myopathy, myofibrillar, 9, with early respiratory failure dilated cardiomyopathy 1G autosomal recessive limb-girdle muscular dystrophy type 2J early-onset myopathy with fatal cardiomyopathy

Similar variants

TTN p.Phe3990Cys Uncertain significance ★ same residue
TTN c.100171+1G>A Likely pathogenic ★★ same condition
TTN c.100766-1G>T Likely pathogenic ★★ same condition
TTN c.100766-2A>T Likely pathogenic ★★ same condition
TTN c.106375-2A>G Pathogenic/Likely pathogenic ★★ same condition
TTN c.106531+1G>A Pathogenic/Likely pathogenic ★★ same condition
TTN c.107224-1G>C Pathogenic/Likely pathogenic ★★ same condition
TTN c.107377+1G>A 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-pro3990leu (accessed [today's date]).

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