Is CA8 p.Pro105Ser (c.313C>T) pathogenic?

CA8 p.Pro105Ser (c.313C>T) is classified Uncertain significance in CA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-09). AlphaMissense: ambiguous (0.3681); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with CA8 p.Pro105Ser (c.313C>T)?

CA8 p.Pro105Ser (c.313C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CA8 p.Pro105Ser (c.313C>T) in the general population?

CA8 p.Pro105Ser (c.313C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CA8 p.Pro105Ser (c.313C>T)?

AlphaMissense predicts ambiguous (score 0.3681) — an in-silico prediction, not a clinical call.

CA8 p.Pro105Ser

c.313C>T · rs1488227064 · VCV1728064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3681	ambiguous
REVEL	0.271	benign-leaning
SaProt	LLR -11.54	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.24 · regional, not allelic
Overall
CADD	24.7	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 0.00891% East Asian · 4/44,876 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000744% 12/1,613,434 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,219
European (non-Finnish)	0.000678%	147,439

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.Pro105Ser
Coding: c.313C>T
MANE Select: NM_004056
dbSNP: rs1488227064
Type: single nucleotide variant
Location: chr8:60266029 (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 105: 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-pro105ser (accessed [today's date]).

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