Is TTN p.Ser9237Ala (c.27709T>G) pathogenic?

TTN p.Ser9237Ala (c.27709T>G) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-04-09). AlphaMissense: likely benign (0.1059); Ultra-rare (popmax 0.0825%, eas); Associated with dilated cardiomyopathy 1G.

What condition is associated with TTN p.Ser9237Ala (c.27709T>G)?

TTN p.Ser9237Ala (c.27709T>G) is associated with dilated cardiomyopathy 1G, autosomal recessive limb-girdle muscular dystrophy type 2J (ClinVar).

How common is TTN p.Ser9237Ala (c.27709T>G) in the general population?

TTN p.Ser9237Ala (c.27709T>G) is ultra-rare (popmax 0.0825%, eas) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TTN p.Ser9237Ala (c.27709T>G)?

AlphaMissense predicts likely benign (score 0.1059) — an in-silico prediction, not a clinical call.

TTN p.Ser9237Ala

c.27709T>G · rs766638714 · VCV203351

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

dilated cardiomyopathy 1G

Computational evidence

Protein change
AlphaMissense	0.1059	likely benign
REVEL	0.23	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 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	21.6	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 S8920A vs ClinVar S9237A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0825% East Asian · 37/44,872 alleles

Filtering AF 0.0615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.00248% 40/1,613,682 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0825%	1,213
Remaining individualsnot grpmax-eligible	0.0048%	20,819

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.Ser9237Ala
Coding: c.27709T>G
MANE Select: NM_001267550
dbSNP: rs766638714
Type: single nucleotide variant
Location: chr2:178712121 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 9237: the ig-like 75 domain

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

Disease context

dilated cardiomyopathy 1G — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2J

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

TTN p.Ser9237= Likely benign ★★ same residue
TTN p.Ser9237Pro 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

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-ser9237ala (accessed [today's date]).

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