Is CAT p.His466Pro (c.1397A>C) pathogenic?

CAT p.His466Pro (c.1397A>C) is classified Uncertain significance in CAT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: likely pathogenic (0.654); Ultra-rare (popmax 0.032%, afr).

How common is CAT p.His466Pro (c.1397A>C) in the general population?

CAT p.His466Pro (c.1397A>C) is ultra-rare (popmax 0.032%, afr) (gnomAD).

What do computational predictors say about CAT p.His466Pro (c.1397A>C)?

AlphaMissense predicts likely pathogenic (score 0.654) — an in-silico prediction, not a clinical call.

CAT p.His466Pro

c.1397A>C · rs370234500 · VCV2384890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.654 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.654	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -12.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 32 kb · p 0.47 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.032% African / African-American · 24/75,050 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00149% 24/1,614,152 alleles · ultra-rare

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.His466Pro
Coding: c.1397A>C
MANE Select: NM_001752
dbSNP: rs370234500
Type: single nucleotide variant
Location: chr11:34468358 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.97 · 17 PDB
Residue 466: an α-helix

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

Similar variants

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
CAT p.His492= Benign/Likely benign ★★ same type
CAT p.Ile109= Benign/Likely benign ★★ same type
CAT p.Phe185= Benign/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-his466pro (accessed [today's date]).

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