Is CA8 p.Ser56= (c.168A>G) pathogenic?

CA8 p.Ser56= (c.168A>G) is classified Likely benign in CA8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-01). Very rare (popmax 0.000254%, nfe).

How common is CA8 p.Ser56= (c.168A>G) in the general population?

CA8 p.Ser56= (c.168A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

CA8 p.Ser56=

c.168A>G · VCV3257436

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

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 -2.2	GERP -3.3
Overall
CADD	4.929	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,958 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,914 alleles · very rare

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.Ser56=
Coding: c.168A>G
MANE Select: NM_004056
Type: single nucleotide variant
Location: chr8:60279813 (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 56: the alpha-carbonic anhydrase domain; an α-helix

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

Similar variants

CA8 p.Arg213Trp Uncertain significance ★★ ⚠ same type
CA8 p.Pro14Arg Uncertain significance ★★ ⚠ same type
CA8 p.Ser71Phe Uncertain significance ★★ ⚠ same type
CA8 c.100+154T>C Benign ★★ same type
CA8 c.100+19G>A Benign ★★ same type
CA8 c.100+37G>A Benign ★★ same type
CA8 c.100+81C>T Benign ★★ same type
CA8 c.100+85T>C Benign ★★ 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/ca8-p-ser56 (accessed [today's date]).

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