Is TCAP p.Arg153His (c.458G>A) pathogenic?

TCAP p.Arg153His (c.458G>A) is classified Conflicting classifications of pathogenicity in TCAP (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0749); Rare (popmax 0.107%, eas); Associated with hypertrophic cardiomyopathy 25.

What condition is associated with TCAP p.Arg153His (c.458G>A)?

TCAP p.Arg153His (c.458G>A) is associated with hypertrophic cardiomyopathy 25, autosomal recessive limb-girdle muscular dystrophy type 2G, familial hypertrophic cardiomyopathy (ClinVar).

How common is TCAP p.Arg153His (c.458G>A) in the general population?

TCAP p.Arg153His (c.458G>A) is rare (popmax 0.107%, eas) (gnomAD).

What do computational predictors say about TCAP p.Arg153His (c.458G>A)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

TCAP p.Arg153His

c.458G>A · rs149585781 · VCV44710

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypertrophic cardiomyopathy 25

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.517	indeterminate
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -2.1, phastCons 0.2
Regional constraint	o/e 0.95	unconstrained · MANE · 746 bp · p 0.44 · regional, not allelic
Overall
CADD	17.85	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.107% East Asian · 48/44,878 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.0203% 325/1,603,976 alleles · rare exomes 293/1,451,644 · genomes 32/152,332 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.228%	439
East Asiangrpmax	0.107%	935
Remaining individualsnot grpmax-eligible	0.0176%	5,675
Middle Eastern	0.0165%	6,060
European (non-Finnish)	0.0118%	8,488
South Asian	0.0022%	45,537
African / African-American	0.00133%	75,054

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: TCAP
Protein: p.Arg153His
Coding: c.458G>A
MANE Select: NM_003673
dbSNP: rs149585781
Type: single nucleotide variant
Location: chr17:39666063 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.89 · 2 PDB
Residue 153: the 'disordered' region; a UniProt-annotated variant site (in cmh25)

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.Arg153Cys Uncertain significance ★★ ⚠ same residue
TCAP p.Arg153Ser Uncertain significance ★★ ⚠ same residue
TCAP p.Arg153Pro Uncertain significance ★ ⚠ same residue
TCAP p.Arg153fs 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

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-arg153his (accessed [today's date]).

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