Is CIROP p.Arg22Ter (c.64C>T) pathogenic?

CIROP p.Arg22Ter (c.64C>T) is classified Conflicting classifications of pathogenicity in CIROP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-01). Ultra-rare (popmax 0.0229%, mid); Associated with heterotaxy, visceral, 12, autosomal.

What condition is associated with CIROP p.Arg22Ter (c.64C>T)?

CIROP p.Arg22Ter (c.64C>T) is associated with heterotaxy, visceral, 12, autosomal (ClinVar).

How common is CIROP p.Arg22Ter (c.64C>T) in the general population?

CIROP p.Arg22Ter (c.64C>T) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

CIROP p.Arg22Ter

c.64C>T · rs185661693 · VCV2442172

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Conditions

heterotaxy, visceral, 12, autosomal

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 16
Splicing
SpliceAI	Δ0.26	donor loss, 29 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.96	GERP -1.5, phastCons 0.98
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0229% Middle Eastern · 1/4,362 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0142%

Overall 0.0133% 93/700,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,362
European (non-Finnish)	0.019%	5,261
Remaining individualsnot grpmax-eligible	0.0153%	6,530
Admixed American	0.0141%	7,094
African / African-American	0.007%	14,281
South Asian	0.00297%	33,693
Finnishnot grpmax-eligible	0.00226%	44,230

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: CIROP
Protein: p.Arg22Ter
Coding: c.64C>T
MANE Select: NM_001354640
dbSNP: rs185661693
Type: single nucleotide variant
Location: chr14:23104857 (GRCh38)
Structure: AlphaFold pLDDT 73.73

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

Disease context

heterotaxy, visceral, 12, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIROP p.Gln528Ter Likely pathogenic ★ same condition
CIROP p.Gly180Arg Uncertain significance ★ ⚠ same condition
CIROP p.Gly511Glu Uncertain significance ★ same condition
CIROP p.Ser31Phe Conflicting classifications of pathogenicity ★ ⚠ same condition
CIROP p.Tyr68Cys Uncertain significance ★ ⚠ same condition
CIROP p.Arg191Ter Pathogenic same condition
CIROP p.Arg389Ile Pathogenic same condition
CIROP p.Ser384Leu 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/cirop-p-arg22ter (accessed [today's date]).

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