Is CA8 p.Ser228Gly (c.682A>G) pathogenic?

CA8 p.Ser228Gly (c.682A>G) is classified Uncertain significance in CA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2366); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CA8 p.Ser228Gly (c.682A>G)?

CA8 p.Ser228Gly (c.682A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CA8 p.Ser228Gly (c.682A>G) in the general population?

CA8 p.Ser228Gly (c.682A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CA8 p.Ser228Gly (c.682A>G)?

AlphaMissense predicts likely benign (score 0.2366) — an in-silico prediction, not a clinical call.

CA8 p.Ser228Gly

c.682A>G · VCV4601977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2366 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2366	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -11.47	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 57 kb · p 0.00026 · regional, not allelic
Overall
CADD	26.9	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

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: CA8
Protein: p.Ser228Gly
Coding: c.682A>G
MANE Select: NM_004056
Type: single nucleotide variant
Location: chr8:60222705 (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 228: 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

Similar variants

CA8 p.Pro14Arg Uncertain significance ★★ ⚠ same condition
CA8 p.Ser71Phe Uncertain significance ★★ ⚠ same condition
CA8 c.576+5G>A Benign/Likely benign ★★ same condition
CA8 p.Glu109= Benign ★★ same condition
CA8 p.Glu22= Benign ★★ same condition
CA8 p.Gly265= Benign/Likely benign ★★ same condition
CA8 p.Leu112= Benign ★★ same condition
CA8 p.Pro103= 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-ser228gly (accessed [today's date]).

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