Is TTN p.Pro30723Ser (c.92167C>T) pathogenic?

TTN p.Pro30723Ser (c.92167C>T) is classified Uncertain significance in TTN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-21). AlphaMissense: likely pathogenic (0.965); Ultra-rare (popmax 0.0118%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2J.

What condition is associated with TTN p.Pro30723Ser (c.92167C>T)?

TTN p.Pro30723Ser (c.92167C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2J, tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure (ClinVar).

How common is TTN p.Pro30723Ser (c.92167C>T) in the general population?

TTN p.Pro30723Ser (c.92167C>T) is ultra-rare (popmax 0.0118%, nfe) (gnomAD).

How is Titin-related limb-girdle muscular dystrophy R10 inherited?

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

What do computational predictors say about TTN p.Pro30723Ser (c.92167C>T)?

AlphaMissense predicts likely pathogenic (score 0.965) — an in-silico prediction, not a clinical call.

TTN p.Pro30723Ser

c.92167C>T · rs758537709 · VCV856860

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.965 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2J

Computational evidence

Protein change
AlphaMissense	0.965	likely pathogenic · top 9% in TTN
REVEL	0.861	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P29082S vs ClinVar P30723S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0118% European (non-Finnish) · 139/1,173,536 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00961%

Overall 0.00954% 153/1,604,290 alleles · ultra-rare exomes 139/1,452,150 · genomes 14/152,140 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0173%	5,787
European (non-Finnish)grpmax	0.0118%	8,443
Remaining individualsnot grpmax-eligible	0.00484%	20,656

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro30723Ser
Coding: c.92167C>T
MANE Select: NM_001267550
dbSNP: rs758537709
Type: single nucleotide variant
Location: chr2:178549459 (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

autosomal recessive limb-girdle muscular dystrophy type 2J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tibial muscular dystrophy myopathy, myofibrillar, 9, with early respiratory failure dilated cardiomyopathy 1G early-onset myopathy with fatal cardiomyopathy hypertrophic cardiomyopathy 9

For Titin-related limb-girdle muscular dystrophy R10 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

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-pro30723ser (accessed [today's date]).

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