Is CA12 p.Phe76= (c.228C>T) pathogenic?

CA12 p.Phe76= (c.228C>T) is classified Benign in CA12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Low-frequency (popmax 1.69%, afr); Associated with isolated hyperchlorhidrosis.

What condition is associated with CA12 p.Phe76= (c.228C>T)?

CA12 p.Phe76= (c.228C>T) is associated with isolated hyperchlorhidrosis (ClinVar).

How common is CA12 p.Phe76= (c.228C>T) in the general population?

CA12 p.Phe76= (c.228C>T) is low-frequency (popmax 1.69%, afr) (gnomAD).

How is Isolated hyperchlorhidrosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CA12 p.Phe76=

c.228C>T · rs139241902 · VCV710051

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.69%, afr)

Conditions

isolated hyperchlorhidrosis

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 2.8	GERP 2.1, phastCons 1
Overall
CADD	8.169	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.69% African / African-American · 1,267/74,966 alleles

Filtering AF 1.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.58%

Overall 0.099% 1,597/1,613,580 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.69%	59
Middle Eastern	0.182%	551
Admixed American	0.16%	625
Remaining individualsnot grpmax-eligible	0.15%	665
Finnishnot grpmax-eligible	0.011%	9,129
European (non-Finnish)	0.0102%	9,832
South Asian	0.0022%	45,525

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: CA12
Protein: p.Phe76=
Coding: c.228C>T
MANE Select: NM_001218
dbSNP: rs139241902
Type: single nucleotide variant
Location: chr15:63346588 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.50 · 40 PDB
Residue 76: a disulfide bond; a β-strand; the alpha-carbonic anhydrase domain

Full CA12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

isolated hyperchlorhidrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isolated hyperchlorhidrosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CA12 p.Glu143Lys Likely pathogenic ★ same condition
CA12 p.His121Gln Pathogenic ★ same condition
CA12 p.Tyr195Ter Likely pathogenic ★ same condition
CA12 c.908-1G>A Conflicting classifications of pathogenicity ★ same condition
CA12 p.Gly223Ala Uncertain significance ★ ⚠ same condition
CA12 p.His119Tyr Uncertain significance ★ ⚠ same condition
CA12 p.Pro229fs Likely pathogenic ★ same condition
CA12 p.Thr287fs Pathogenic ★ 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/ca12-p-phe76 (accessed [today's date]).

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