Is TTN p.Ser367Pro (c.1099T>C) pathogenic?

TTN p.Ser367Pro (c.1099T>C) is classified Conflicting classifications of pathogenicity in TTN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-09). AlphaMissense: likely benign (0.1242); Very rare (popmax 0.00659%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Ser367Pro (c.1099T>C)?

TTN p.Ser367Pro (c.1099T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Ser367Pro (c.1099T>C) in the general population?

TTN p.Ser367Pro (c.1099T>C) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about TTN p.Ser367Pro (c.1099T>C)?

AlphaMissense predicts likely benign (score 0.1242) — an in-silico prediction, not a clinical call.

TTN p.Ser367Pro

c.1099T>C · rs376015894 · VCV1791633

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1242	likely benign
REVEL	0.045	moderately 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 2.8	GERP -4.2, phastCons 0.97
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	16.89	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,084 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00186% 30/1,613,892 alleles · very rare exomes 26/1,461,624 · genomes 4/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,181
European (non-Finnish)	0.00195%	51,304
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ser367Pro
Coding: c.1099T>C
MANE Select: NM_001267550
dbSNP: rs376015894
Type: single nucleotide variant
Location: chr2:178795068 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TTN p.Ser367= Likely benign ★ 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
TTN p.Arg1012Ter 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-ser367pro (accessed [today's date]).

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