Is CA1 p.Pro22Ser (c.64C>T) pathogenic?

CA1 p.Pro22Ser (c.64C>T) is classified Uncertain significance in CA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-27). AlphaMissense: ambiguous (0.3509); Very rare (popmax 0.00949%, nfe).

How common is CA1 p.Pro22Ser (c.64C>T) in the general population?

CA1 p.Pro22Ser (c.64C>T) is very rare (popmax 0.00949%, nfe) (gnomAD).

What do computational predictors say about CA1 p.Pro22Ser (c.64C>T)?

AlphaMissense predicts ambiguous (score 0.3509) — an in-silico prediction, not a clinical call.

CA1 p.Pro22Ser

c.64C>T · rs775760764 · VCV2365877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00949%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3509	ambiguous
REVEL	0.59	indeterminate
SaProt	LLR -9.18	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 0.86, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 13 kb · p 0.16 · regional, not allelic
Overall
CADD	22.3	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 0.00949% European (non-Finnish) · 112/1,179,814 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.00706% 114/1,613,716 alleles · very rare exomes 108/1,461,612 · genomes 6/152,104 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00949%	10,534
Remaining individualsnot grpmax-eligible	0.0032%	31,240

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: CA1
Protein: p.Pro22Ser
Coding: c.64C>T
MANE Select: NM_001128831
dbSNP: rs775760764
Type: single nucleotide variant
Location: chr8:85338423 (GRCh38)
Gene constraint: LOEUF 1.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.97 · 57 PDB
Residue 22: the alpha-carbonic anhydrase domain; an α-helix; the 'disordered' region

Full CA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA1 p.Pro22Leu Uncertain significance ★ same residue
CA1 p.Ala143Val Benign ★★ ⚠ same type
CA1 p.Ala167Val Benign ★★ same type
CA1 p.His120= Benign ★★ same type
CA1 p.Pro196Leu Benign ★★ same type
CA1 p.Ala154Gly Uncertain significance ★ ⚠ same type
CA1 p.Ala259Pro Uncertain significance ★ ⚠ same type
CA1 p.Arg228Cys 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/ca1-p-pro22ser (accessed [today's date]).

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