Is CA9 p.Leu418Pro (c.1253T>C) pathogenic?

CA9 p.Leu418Pro (c.1253T>C) is classified Uncertain significance in CA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: ambiguous (0.5148); Ultra-rare (popmax 0.0164%, mid).

How common is CA9 p.Leu418Pro (c.1253T>C) in the general population?

CA9 p.Leu418Pro (c.1253T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CA9 p.Leu418Pro (c.1253T>C)?

AlphaMissense predicts ambiguous (score 0.5148) — an in-silico prediction, not a clinical call.

CA9 p.Leu418Pro

c.1253T>C · VCV4647412

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5148 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Computational evidence

Protein change
AlphaMissense	0.5148	ambiguous
REVEL	0.505	indeterminate
SaProt	LLR -13.30	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 7,062 bp · p 0.76 · regional, not allelic
Overall
CADD	27.7	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 0.0164% Middle Eastern · 1/6,082 alleles

Overall 0.000124% 2/1,614,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	8.47e-05%	1,180,027

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.Leu418Pro
Coding: c.1253T>C
MANE Select: NM_001216
Type: single nucleotide variant
Location: chr9:35680768 (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-leu418pro (accessed [today's date]).

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