Is CA4 p.Ile56= (c.168C>T) pathogenic?

CA4 p.Ile56= (c.168C>T) is classified Likely benign in CA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-12). Very rare (popmax 0.00667%, amr).

How common is CA4 p.Ile56= (c.168C>T) in the general population?

CA4 p.Ile56= (c.168C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

CA4 p.Ile56=

c.168C>T · rs771929990 · VCV1113040

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

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 -7.5	GERP -4
Overall
CADD	1.087	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,012 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00304% 49/1,613,824 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,413
Admixed Americangrpmax	0.00667%	15,003
South Asian	0.00439%	22,770
European (non-Finnish)	0.00297%	33,708

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile56=
Coding: c.168C>T
MANE Select: NM_000717
dbSNP: rs771929990
Type: single nucleotide variant
Location: chr17:60156615 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 56: a disulfide bond; 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-ile56 (accessed [today's date]).

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