Is CA8 p.Ser100Leu (c.299C>T) pathogenic?

CA8 p.Ser100Leu (c.299C>T) is classified Benign in CA8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1083); Low-frequency (popmax 2.57%, afr); Associated with Inborn genetic diseases.

What condition is associated with CA8 p.Ser100Leu (c.299C>T)?

CA8 p.Ser100Leu (c.299C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CA8 p.Ser100Leu (c.299C>T) in the general population?

CA8 p.Ser100Leu (c.299C>T) is low-frequency (popmax 2.57%, afr) (gnomAD).

What do computational predictors say about CA8 p.Ser100Leu (c.299C>T)?

AlphaMissense predicts likely benign (score 0.1083) — an in-silico prediction, not a clinical call.

CA8 p.Ser100Leu

c.299C>T · rs149391728 · VCV128539

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1083 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.57%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1083	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -7.91	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 8.5	GERP 0.92, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.24 · regional, not allelic
Overall
CADD	24.5	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 2.57% African / African-American · 1,926/74,928 alleles

Filtering AF 2.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.44%

Overall 0.143% 2,305/1,613,094 alleles · low-frequency exomes 1,160/1,461,064 · genomes 1,145/152,030 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.57%	39
Admixed American	0.228%	438
Remaining individualsnot grpmax-eligible	0.186%	539
Middle Eastern	0.149%	673
European (non-Finnish)	0.00958%	10,438
South Asian	0.0044%	22,743

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.Ser100Leu
Coding: c.299C>T
MANE Select: NM_004056
dbSNP: rs149391728
Type: single nucleotide variant
Location: chr8:60266043 (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 100: the alpha-carbonic anhydrase domain; a β-strand; a UniProt-annotated variant site (in scar34; affects protein stability owing to accelerated proteasomal degradation)

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.Ser100Pro Pathogenic same residue
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

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-ser100leu (accessed [today's date]).

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