Is CA9 p.Pro283Leu (c.848C>T) pathogenic?

CA9 p.Pro283Leu (c.848C>T) is classified Uncertain significance in CA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1084); Very rare (popmax 0.00534%, afr).

How common is CA9 p.Pro283Leu (c.848C>T) in the general population?

CA9 p.Pro283Leu (c.848C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CA9 p.Pro283Leu (c.848C>T)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

CA9 p.Pro283Leu

c.848C>T · rs773530795 · VCV2306735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -8.34	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 5.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 7,062 bp · p 0.76 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00534% African / African-American · 4/74,904 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00204% 33/1,613,786 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,726
Remaining individualsnot grpmax-eligible	0.0032%	31,240
East Asian	0.00223%	44,892
European (non-Finnish)	0.00212%	47,193
Admixed American	0.00167%	59,988

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.Pro283Leu
Coding: c.848C>T
MANE Select: NM_001216
dbSNP: rs773530795
Type: single nucleotide variant
Location: chr9:35677797 (GRCh38)
Gene constraint: LOEUF 1.021 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.13 · 32 PDB
Residue 283: a disulfide bond; the alpha-carbonic anhydrase domain; the 'catalytic' region

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-pro283leu (accessed [today's date]).

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