Is TCAP p.Leu89= (c.267G>A) pathogenic?

TCAP p.Leu89= (c.267G>A) is classified Likely benign in TCAP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-06). Ultra-rare (popmax 0.0165%, mid); Associated with hypertrophic cardiomyopathy 25.

What condition is associated with TCAP p.Leu89= (c.267G>A)?

TCAP p.Leu89= (c.267G>A) is associated with hypertrophic cardiomyopathy 25, autosomal recessive limb-girdle muscular dystrophy type 2G, familial hypertrophic cardiomyopathy (ClinVar).

How common is TCAP p.Leu89= (c.267G>A) in the general population?

TCAP p.Leu89= (c.267G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

TCAP p.Leu89=

c.267G>A · rs1419129039 · VCV509098

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

hypertrophic cardiomyopathy 25

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 1.3	GERP 0.4, phastCons 1
Overall
CADD	5.045	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00223% 36/1,611,198 alleles · ultra-rare exomes 33/1,459,000 · genomes 3/152,198 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
Remaining individualsnot grpmax-eligible	0.00321%	31,191
European (non-Finnish)	0.0028%	35,739

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: TCAP
Protein: p.Leu89=
Coding: c.267G>A
MANE Select: NM_003673
dbSNP: rs1419129039
Type: single nucleotide variant
Location: chr17:39665872 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.89 · 2 PDB

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

Disease context

hypertrophic cardiomyopathy 25 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2G familial hypertrophic cardiomyopathy

Similar variants

TCAP p.Leu89Met Uncertain significance ★ ⚠ same residue
TCAP c.110+5G>T Likely pathogenic ★★ same condition
TCAP p.Cys57Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP p.Gln53Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP p.Glu35Ter Pathogenic ★★ same condition
TCAP p.Trp22Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP p.Trp25Ter Pathogenic/Likely pathogenic ★★ same condition
TCAP c.110+4A>G Uncertain significance ★★ 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/tcap-p-leu89 (accessed [today's date]).

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