Is CA9 p.Arg450His (c.1349G>A) pathogenic?

CA9 p.Arg450His (c.1349G>A) is classified Likely benign in CA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0581); Ultra-rare (popmax 0.0226%, nfe).

How common is CA9 p.Arg450His (c.1349G>A) in the general population?

CA9 p.Arg450His (c.1349G>A) is ultra-rare (popmax 0.0226%, nfe) (gnomAD).

What do computational predictors say about CA9 p.Arg450His (c.1349G>A)?

AlphaMissense predicts likely benign (score 0.0581) — an in-silico prediction, not a clinical call.

CA9 p.Arg450His

c.1349G>A · VCV3483774

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0581 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0581	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -3.5, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 7,062 bp · p 0.76 · regional, not allelic
Overall
CADD	3.185	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 0.0226% European (non-Finnish) · 267/1,180,014 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0179% 289/1,613,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0226%	4,420
African / African-American	0.016%	6,241
Remaining individualsnot grpmax-eligible	0.0096%	10,413
South Asian	0.0022%	45,530
Admixed American	0.00167%	59,978
Finnishnot grpmax-eligible	0.00156%	63,962

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: CA9
Protein: p.Arg450His
Coding: c.1349G>A
MANE Select: NM_001216
Type: single nucleotide variant
Location: chr9:35680994 (GRCh38)
Gene constraint: LOEUF 1.021 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.13 · 32 PDB

Full CA9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA9 p.Pro114= Benign ★★ same type
CA9 p.Ala155Thr Uncertain significance ★ ⚠ same type
CA9 p.Ala176Val Uncertain significance ★ ⚠ same type
CA9 p.Ala232Val Uncertain significance ★ ⚠ same type
CA9 p.Ala300Ser Uncertain significance ★ ⚠ same type
CA9 p.Ala353Thr Uncertain significance ★ ⚠ same type
CA9 p.Ala377Glu Uncertain significance ★ ⚠ same type
CA9 p.Ala425Ser Uncertain significance ★ ⚠ 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/ca9-p-arg450his (accessed [today's date]).

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