Is TTN p.Ser16640Thr (c.49919G>C) pathogenic?

TTN p.Ser16640Thr (c.49919G>C) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1574); Low-frequency (popmax 2.13%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Ser16640Thr (c.49919G>C)?

TTN p.Ser16640Thr (c.49919G>C) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy (ClinVar).

How common is TTN p.Ser16640Thr (c.49919G>C) in the general population?

TTN p.Ser16640Thr (c.49919G>C) is low-frequency (popmax 2.13%, sas) (gnomAD).

What do computational predictors say about TTN p.Ser16640Thr (c.49919G>C)?

AlphaMissense predicts likely benign (score 0.1574) — an in-silico prediction, not a clinical call.

TTN p.Ser16640Thr

c.49919G>C · rs55663050 · VCV47036

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.1574 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.13%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1574	likely benign
REVEL	0.233	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 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 37 kb · p 6.3e-14 · regional, not allelic
Overall
CADD	21.4	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 S14999T vs ClinVar S16640T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.13% South Asian · 1,933/90,892 alleles

Filtering AF 2.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.02%

Overall 0.22% 3,545/1,612,008 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.13%	47
Middle Eastern	0.414%	242
Remaining individualsnot grpmax-eligible	0.295%	339
European (non-Finnish)	0.109%	918
Admixed American	0.0986%	1,014
Ashkenazi Jewishnot grpmax-eligible	0.0846%	1,182
African / African-American	0.032%	3,122
East Asian	0.0157%	6,360
Finnishnot grpmax-eligible	0.00625%	15,988

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.Ser16640Thr
Coding: c.49919G>C
MANE Select: NM_001267550
dbSNP: rs55663050
Type: single nucleotide variant
Location: chr2:178612802 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 16640: the fibronectin type-iii 21 domain; the 'disordered' region

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

Also linked: cardiomyopathy dilated 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 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
TTN c.107377+1G>C 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-ser16640thr (accessed [today's date]).

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