Is TTN p.Pro30331Ser (c.90991C>T) pathogenic?

TTN p.Pro30331Ser (c.90991C>T) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-10-21). AlphaMissense: likely pathogenic (0.9726); Ultra-rare (popmax 0.0867%, afr); Associated with dilated cardiomyopathy 1G.

What condition is associated with TTN p.Pro30331Ser (c.90991C>T)?

TTN p.Pro30331Ser (c.90991C>T) is associated with dilated cardiomyopathy 1G, autosomal recessive limb-girdle muscular dystrophy type 2J (ClinVar).

How common is TTN p.Pro30331Ser (c.90991C>T) in the general population?

TTN p.Pro30331Ser (c.90991C>T) is ultra-rare (popmax 0.0867%, afr) (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.Pro30331Ser (c.90991C>T)?

AlphaMissense predicts likely pathogenic (score 0.9726) — an in-silico prediction, not a clinical call.

TTN p.Pro30331Ser

c.90991C>T · rs75022916 · VCV202973

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0867%, afr)

Conditions

dilated cardiomyopathy 1G

Computational evidence

Protein change
AlphaMissense	0.9726	likely pathogenic
REVEL	0.468	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 75 kb · p 3.1e-23 · regional, not allelic
Overall
CADD	21.7	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 P28690S vs ClinVar P30331S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0867% African / African-American · 65/75,006 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0636%

Overall 0.00434% 70/1,613,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0867%	1,154
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Admixed American	0.00333%	29,995

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.Pro30331Ser
Coding: c.90991C>T
dbSNP: rs75022916
Type: single nucleotide variant
Location: chr2:178551909 (GRCh38)

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)

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-pro30331ser (accessed [today's date]).

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