Is CA9 p.Arg370Trp (c.1108C>T) pathogenic?

CA9 p.Arg370Trp (c.1108C>T) is classified Uncertain significance in CA9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: likely benign (0.1386); Very rare (popmax 0.00446%, eas).

How common is CA9 p.Arg370Trp (c.1108C>T) in the general population?

CA9 p.Arg370Trp (c.1108C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CA9 p.Arg370Trp (c.1108C>T)?

AlphaMissense predicts likely benign (score 0.1386) — an in-silico prediction, not a clinical call.

CA9 p.Arg370Trp

c.1108C>T · VCV3262609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1386 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1386	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -10.23	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.84 · evaluated, not missing
Pangolin	Δ0.26	loss · gain 0.23 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 3.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 7,062 bp · p 0.76 · regional, not allelic
Overall
CADD	28.1	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 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000868% 14/1,613,070 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,445
Admixed American	0.00167%	59,770
European (non-Finnish)	0.000932%	107,240

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.Arg370Trp
Coding: c.1108C>T
MANE Select: NM_001216
Type: single nucleotide variant
Location: chr9:35679896 (GRCh38)
Gene constraint: LOEUF 1.021 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.13 · 32 PDB
Residue 370: 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.Arg370Gly Uncertain significance ★ ⚠ same residue
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

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-arg370trp (accessed [today's date]).

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