Is CA8 p.Glu109= (c.327A>G) pathogenic?

CA8 p.Glu109= (c.327A>G) is classified Benign in CA8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2022-03-24). Common (popmax 77.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with CA8 p.Glu109= (c.327A>G)?

CA8 p.Glu109= (c.327A>G) is associated with Inborn genetic diseases, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3 (ClinVar).

CA8 p.Glu109=

Q: How common is CA8 p.Glu109= (c.327A>G) in the general population?

CA8 p.Glu109= (c.327A>G) is common (popmax 77.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.327A>G · rs7464181 · VCV128540

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 77.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.065	GERP -3.5, phastCons 0.86
Overall
CADD	6.934	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 77.3% African / African-American · 57,935/74,920 alleles

Filtering AF 76.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 76.6%

Overall 42.6% 686,421/1,612,348 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	77.3%	1
Amishnot grpmax-eligible	47.6%	2
Ashkenazi Jewishnot grpmax-eligible	46.8%	2
Middle Eastern	44.8%	2
Remaining individualsnot grpmax-eligible	43.9%	2
South Asian	42.9%	2
Finnishnot grpmax-eligible	42.1%	2
European (non-Finnish)	41.3%	2
Admixed American	34.9%	3
East Asian	22.8%	4

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: CA8
Protein: p.Glu109=
Coding: c.327A>G
MANE Select: NM_004056
dbSNP: rs7464181
Type: single nucleotide variant
Location: chr8:60266015 (GRCh38)
Gene constraint: LOEUF 0.698 · pLI 0.24 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.51 · 1 PDB
Residue 109: the alpha-carbonic anhydrase domain

Full CA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3

Similar variants

CA8 p.Pro14Arg Uncertain significance ★★ ⚠ same condition
CA8 p.Ser71Phe Uncertain significance ★★ ⚠ same condition
CA8 c.100+85T>C Benign ★★ same condition
CA8 c.576+5G>A Benign/Likely benign ★★ same condition
CA8 c.-103T>C Benign ★★ same condition
CA8 c.-54A>C Benign ★★ same condition
CA8 p.Glu22= Benign ★★ same condition
CA8 p.Gly265= Benign/Likely benign ★★ same condition

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/ca8-p-glu109 (accessed [today's date]).

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