Is CAT p.Arg66Ter (c.196C>T) pathogenic?

CAT p.Arg66Ter (c.196C>T) is classified Likely pathogenic in CAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-15). Ultra-rare (popmax 0.0111%, eas); Associated with acatalasia.

What condition is associated with CAT p.Arg66Ter (c.196C>T)?

CAT p.Arg66Ter (c.196C>T) is associated with acatalasia (ClinVar).

How common is CAT p.Arg66Ter (c.196C>T) in the general population?

CAT p.Arg66Ter (c.196C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

How is Acatalasemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CAT p.Arg66Ter

c.196C>T · VCV4845759

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

acatalasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.84, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,870 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.0013% 21/1,614,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,974
European (non-Finnish)	0.00136%	73,747

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: CAT
Protein: p.Arg66Ter
Coding: c.196C>T
MANE Select: NM_001752
Type: single nucleotide variant
Location: chr11:34449321 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.97 · 17 PDB

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

Disease context

acatalasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Acatalasemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CAT c.1056+1G>C Conflicting classifications of pathogenicity ★ same condition
CAT c.903+5G>T Conflicting classifications of pathogenicity ★ same condition
CAT p.Ile69fs Pathogenic same condition
CAT c.239-5G>A Benign/Likely benign ★★ same type
CAT p.Arg189Cys Benign/Likely benign ★★ ⚠ same type
CAT p.Asn439= Likely benign ★★ same type
CAT p.Gly390Asp Benign ★★ same type
CAT p.His209Tyr Likely benign ★★ same type

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/cat-p-arg66ter (accessed [today's date]).

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