Is CA4 p.Gly125= (c.375C>T) pathogenic?

CA4 p.Gly125= (c.375C>T) is classified Benign/Likely benign in CA4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-21). Rare (popmax 0.621%, afr); Associated with retinitis pigmentosa.

What condition is associated with CA4 p.Gly125= (c.375C>T)?

CA4 p.Gly125= (c.375C>T) is associated with retinitis pigmentosa (ClinVar).

How common is CA4 p.Gly125= (c.375C>T) in the general population?

CA4 p.Gly125= (c.375C>T) is rare (popmax 0.621%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

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

CA4 p.Gly125=

c.375C>T · rs148870395 · VCV783794

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.621%, afr)

Conditions

retinitis pigmentosa

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 1.1	GERP 0.52, phastCons 1
Overall
CADD	5.191	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.621% African / African-American · 466/75,064 alleles

Filtering AF 0.574% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.556%

Overall 0.0313% 506/1,614,234 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.621%	161
Middle Eastern	0.033%	3,031
Admixed American	0.03%	3,335
Remaining individualsnot grpmax-eligible	0.0256%	3,907
South Asian	0.0011%	91,090
European (non-Finnish)	0.000254%	393,345

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: CA4
Protein: p.Gly125=
Coding: c.375C>T
MANE Select: NM_000717
dbSNP: rs148870395
Type: single nucleotide variant
Location: chr17:60157533 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 125: a disulfide bond; the alpha-carbonic anhydrase domain

Full CA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CA4 p.Gly125Val Uncertain significance ★ ⚠ same residue
CA4 p.Ile54Met Uncertain significance ★★ ⚠ same condition
CA4 p.Phe70Leu Uncertain significance ★★ ⚠ same condition
CA4 c.-24G>C Benign ★★ same condition
CA4 c.-47C>G Benign ★★ same condition
CA4 p.Arg239Gln Benign ★★ same condition
CA4 p.Asn177Lys Benign/Likely benign ★★ ⚠ same condition
CA4 p.Asn269= 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/ca4-p-gly125 (accessed [today's date]).

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