Is CIC p.Pro546= (c.1638C>T) pathogenic?

CIC p.Pro546= (c.1638C>T) is classified Likely benign in CIC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-05-01). Rare (popmax 0.514%, nfe).

How common is CIC p.Pro546= (c.1638C>T) in the general population?

CIC p.Pro546= (c.1638C>T) is rare (popmax 0.514%, nfe) (gnomAD).

CIC p.Pro546=

c.1638C>T · rs189529121 · VCV1285097

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.514%, 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 -15	GERP -2.5
Overall
CADD	0.011	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.514% European (non-Finnish) · 1,162/225,916 alleles

Filtering AF 0.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.48%

Overall 0.345% 1,373/398,376 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.86%	54
European (non-Finnish)grpmax	0.514%	194
Remaining individualsnot grpmax-eligible	0.287%	349
Finnishnot grpmax-eligible	0.191%	524
Admixed American	0.106%	947
Ashkenazi Jewishnot grpmax-eligible	0.0945%	1,058
African / African-American	0.0883%	1,132
South Asian	0.0254%	3,930

Amish 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: CIC
Protein: p.Pro546=
Coding: c.1638C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs189529121
Type: single nucleotide variant
Location: chr19:42273421 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Pro546Leu Uncertain significance ★ same residue
CIC c.3179+1G>A Likely pathogenic ★★ same type
CIC c.3179+1G>T Pathogenic ★★ same type
CIC c.5903-2A>G Likely pathogenic ★★ same type
CIC p.Asn1136Ser Likely pathogenic ★★ same type
CIC p.Gln1134Ter Pathogenic ★★ same type
CIC p.Gln1799Ter Likely pathogenic ★★ same type
SLC25A1 c.821+1G>A Pathogenic ★★ 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/cic-p-pro546 (accessed [today's date]).

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