Is CA4 p.Leu37= (c.111G>A) pathogenic?

CA4 p.Leu37= (c.111G>A) is classified Uncertain significance in CA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). Very rare (popmax 8.49e-05%, nfe).

How common is CA4 p.Leu37= (c.111G>A) in the general population?

CA4 p.Leu37= (c.111G>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

CA4 p.Leu37=

c.111G>A · rs943864305 · VCV2974853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

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 0.2	GERP -2.9, phastCons 0.003
Overall
CADD	7.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,248 alleles

Overall 6.22e-05% 1/1,608,128 alleles · very rare exomes 1/1,456,062 · genomes 0/152,066 · joint denominator

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.Leu37=
Coding: c.111G>A
MANE Select: NM_000717
dbSNP: rs943864305
Type: single nucleotide variant
Location: chr17:60155366 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 37: the alpha-carbonic anhydrase domain

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

Similar variants

CA4 c.745-9C>G Uncertain significance ★★ same type
CA4 p.Ala156Val Uncertain significance ★★ ⚠ same type
CA4 p.Ala308Ser Uncertain significance ★★ ⚠ same type
CA4 p.Arg279Pro Uncertain significance ★★ ⚠ same type
CA4 p.Arg50His Uncertain significance ★★ ⚠ same type
CA4 p.Arg50Ser Uncertain significance ★★ ⚠ same type
CA4 p.Asp131Asn Uncertain significance ★★ ⚠ same type
CA4 p.Asp206Glu Uncertain significance ★★ ⚠ same type

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-leu37 (accessed [today's date]).

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