Is CAT p.His235Arg (c.704A>G) pathogenic?

CAT p.His235Arg (c.704A>G) is classified Uncertain significance in CAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.9101); Very rare (popmax 0.00333%, amr).

How common is CAT p.His235Arg (c.704A>G) in the general population?

CAT p.His235Arg (c.704A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CAT p.His235Arg (c.704A>G)?

AlphaMissense predicts likely pathogenic (score 0.9101) — an in-silico prediction, not a clinical call.

CAT p.His235Arg

c.704A>G · VCV4219577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9101	likely pathogenic
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -14.30	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 9.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 32 kb · p 0.47 · regional, not allelic
Overall
CADD	25.7	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 0.00333% Admixed American · 2/59,998 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00031% 5/1,613,774 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,999
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	8.48e-05%	1,179,825

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.His235Arg
Coding: c.704A>G
MANE Select: NM_001752
Type: single nucleotide variant
Location: chr11:34453919 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.97 · 17 PDB
Residue 235: a β-strand

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-his235arg (accessed [today's date]).

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