Is CA3 p.Ala232Thr (c.694G>A) pathogenic?

CA3 p.Ala232Thr (c.694G>A) is classified Uncertain significance in CA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.0739); Rare (popmax 0.837%, afr).

How common is CA3 p.Ala232Thr (c.694G>A) in the general population?

CA3 p.Ala232Thr (c.694G>A) is rare (popmax 0.837%, afr) (gnomAD).

What do computational predictors say about CA3 p.Ala232Thr (c.694G>A)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

CA3 p.Ala232Thr

c.694G>A · VCV4217527

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.837%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -9.11	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 4.5	GERP 0.89, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 9,240 bp · p 0.065 · regional, not allelic
Overall
CADD	15.86	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 0.837% African / African-American · 628/75,036 alleles

Filtering AF 0.783% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.761%

Overall 0.0428% 691/1,613,398 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.837%	119
Remaining individualsnot grpmax-eligible	0.0512%	1,953
Admixed American	0.0417%	2,397
Middle Eastern	0.0331%	3,020
South Asian	0.0011%	90,794
European (non-Finnish)	0.000254%	393,230

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: CA3
Protein: p.Ala232Thr
Coding: c.694G>A
MANE Select: NM_005181
Type: single nucleotide variant
Location: chr8:85448064 (GRCh38)
Gene constraint: LOEUF 1.215 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.99 · 5 PDB
Residue 232: the alpha-carbonic anhydrase domain

Full CA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA3 p.Ala115Glu Uncertain significance ★ ⚠ same type
CA3 p.Arg188Gln Uncertain significance ★ ⚠ same type
CA3 p.Asn62Ser Uncertain significance ★ ⚠ same type
CA3 p.Asp179Gly Uncertain significance ★ ⚠ same type
CA3 p.Glu26Gln Uncertain significance ★ ⚠ same type
CA3 p.Gly82Cys Uncertain significance ★ ⚠ same type
CA3 p.Gly82Ser Uncertain significance ★ ⚠ same type
CA3 p.His10Tyr 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/ca3-p-ala232thr (accessed [today's date]).

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