Is TTN p.Pro324Ser (c.970C>T) pathogenic?

TTN p.Pro324Ser (c.970C>T) is classified Benign/Likely benign in TTN (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.3511); Rare (popmax 0.794%, afr); Associated with cardiomyopathy.

What condition is associated with TTN p.Pro324Ser (c.970C>T)?

TTN p.Pro324Ser (c.970C>T) is associated with cardiomyopathy, long QT syndrome, tibial muscular dystrophy (ClinVar).

How common is TTN p.Pro324Ser (c.970C>T) in the general population?

TTN p.Pro324Ser (c.970C>T) is rare (popmax 0.794%, afr) (gnomAD).

What do computational predictors say about TTN p.Pro324Ser (c.970C>T)?

AlphaMissense predicts ambiguous (score 0.3511) — an in-silico prediction, not a clinical call.

TTN p.Pro324Ser

c.970C>T · rs72647845 · VCV47678

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

ambiguous

0.3511 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.794%, afr)

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.3511	ambiguous
REVEL	0.39	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	21.5	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 0.794% African / African-American · 596/75,034 alleles

Filtering AF 0.742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.721%

Overall 0.0411% 664/1,614,166 alleles · rare exomes 291/1,461,856 · genomes 373/152,310 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.794%	126
Admixed American	0.05%	2,001
Remaining individualsnot grpmax-eligible	0.0368%	2,718
European (non-Finnish)	0.00127%	78,668

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.Pro324Ser
Coding: c.970C>T
MANE Select: NM_001267550
dbSNP: rs72647845
Type: single nucleotide variant
Location: chr2:178795197 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 324: the 'zis1' region

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

Disease context

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

Also linked: long QT syndrome 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.Pro324Leu Uncertain significance ★ same residue
TTN p.Pro324= Likely benign ★ 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-pro324ser (accessed [today's date]).

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