Is TTN p.Pro4186= (c.12558A>G) pathogenic?

TTN p.Pro4186= (c.12558A>G) is classified Benign/Likely benign in TTN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Rare (popmax 0.132%, mid); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Pro4186= (c.12558A>G)?

TTN p.Pro4186= (c.12558A>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1G, autosomal recessive limb-girdle muscular dystrophy type 2J (ClinVar).

How common is TTN p.Pro4186= (c.12558A>G) in the general population?

TTN p.Pro4186= (c.12558A>G) is rare (popmax 0.132%, mid) (gnomAD).

TTN p.Pro4186=

c.12558A>G · rs72648921 · VCV47825

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP 1.2, phastCons 0.025
Overall
CADD	2.587	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,080 alleles

Filtering AF 0.0655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0477%

Overall 0.00452% 73/1,613,722 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	760
European (non-Finnish)	0.00492%	20,341
South Asian	0.00329%	30,360
Remaining individualsnot grpmax-eligible	0.0032%	31,230
Admixed American	0.00167%	59,984
Finnishnot grpmax-eligible	0.00156%	64,022

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.Pro4186=
Coding: c.12558A>G
MANE Select: NM_001267550
dbSNP: rs72648921
Type: single nucleotide variant
Location: chr2:178740675 (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

Also linked: dilated cardiomyopathy 1G autosomal recessive limb-girdle muscular dystrophy type 2J

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-pro4186 (accessed [today's date]).

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