Is TTN p.Arg34883His (c.104648G>A) pathogenic?

TTN p.Arg34883His (c.104648G>A) is classified Uncertain significance in TTN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.6002); Very rare (popmax 0.00534%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Arg34883His (c.104648G>A)?

TTN p.Arg34883His (c.104648G>A) is associated with Cardiovascular phenotype, tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure (ClinVar).

How common is TTN p.Arg34883His (c.104648G>A) in the general population?

TTN p.Arg34883His (c.104648G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about TTN p.Arg34883His (c.104648G>A)?

AlphaMissense predicts likely pathogenic (score 0.6002) — an in-silico prediction, not a clinical call.

TTN p.Arg34883His

c.104648G>A · rs368063908 · VCV1023057

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6002	likely pathogenic
REVEL	0.5	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 75 kb · p 3.1e-23 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R33242H vs ClinVar R34883H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,848 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000992% 16/1,613,428 alleles · very rare exomes 13/1,461,384 · genomes 3/152,044 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,712
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)	0.000932%	107,252

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.Arg34883His
Coding: c.104648G>A
MANE Select: NM_001267550
dbSNP: rs368063908
Type: single nucleotide variant
Location: chr2:178531967 (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: 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 hypertrophic cardiomyopathy 9

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-arg34883his (accessed [today's date]).

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