Is TTN p.Pro21172= (c.63516G>A) pathogenic?

TTN p.Pro21172= (c.63516G>A) is classified Likely benign in TTN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-11). Ultra-rare (popmax 0.0161%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Pro21172= (c.63516G>A)?

TTN p.Pro21172= (c.63516G>A) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1G, autosomal recessive limb-girdle muscular dystrophy type 2J (ClinVar).

How common is TTN p.Pro21172= (c.63516G>A) in the general population?

TTN p.Pro21172= (c.63516G>A) is ultra-rare (popmax 0.0161%, afr) (gnomAD).

TTN p.Pro21172=

c.63516G>A · rs372493799 · VCV699022

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, afr)

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 -9.8	GERP -5.6
Overall
CADD	0.192	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0161% African / African-American · 12/74,452 alleles

Filtering AF 0.00927% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00726%

Overall 0.00238% 38/1,597,232 alleles · ultra-rare exomes 34/1,445,100 · genomes 4/152,132 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0161%	6,204
South Asian	0.00452%	22,115
Admixed American	0.00342%	29,249
Remaining individualsnot grpmax-eligible	0.00324%	30,867
Finnishnot grpmax-eligible	0.00158%	63,372
European (non-Finnish)	0.00145%	68,873

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.Pro21172=
Coding: c.63516G>A
MANE Select: NM_001267550
dbSNP: rs372493799
Type: single nucleotide variant
Location: chr2:178587793 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 21172: the fibronectin type-iii 53 domain

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-pro21172 (accessed [today's date]).

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