Is CA4 p.Pro227Gln (c.680C>A) pathogenic?

CA4 p.Pro227Gln (c.680C>A) is classified Uncertain significance in CA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: likely pathogenic (0.9334); Absent from gnomAD v4.1.

How common is CA4 p.Pro227Gln (c.680C>A) in the general population?

CA4 p.Pro227Gln (c.680C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CA4 p.Pro227Gln (c.680C>A)?

AlphaMissense predicts likely pathogenic (score 0.9334) — an in-silico prediction, not a clinical call.

CA4 p.Pro227Gln

c.680C>A · VCV3691706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9334 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9334	likely pathogenic · top 10% in CA4
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -14.18	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	24.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CA4
Protein: p.Pro227Gln
Coding: c.680C>A
MANE Select: NM_000717
Type: single nucleotide variant
Location: chr17:60158382 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 227: a disulfide bond; the alpha-carbonic anhydrase domain

Full CA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA4 p.Pro227Arg Uncertain significance ★★ ⚠ same residue
CA4 p.Pro227Leu Uncertain significance ★★ ⚠ same residue
CA4 p.Pro227= Conflicting classifications of pathogenicity ★ same residue
CA4 c.745-9C>G Uncertain significance ★★ same type
CA4 p.Ala156Val Uncertain significance ★★ ⚠ same type
CA4 p.Ala308Ser Uncertain significance ★★ ⚠ same type
CA4 p.Arg279Pro Uncertain significance ★★ ⚠ same type
CA4 p.Arg50His 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/ca4-p-pro227gln (accessed [today's date]).

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