Is CIROP p.Gly180Arg (c.538G>C) pathogenic?

CIROP p.Gly180Arg (c.538G>C) is classified Uncertain significance in CIROP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-12). AlphaMissense: likely pathogenic (0.6142); Very rare (popmax 0.00026%, nfe); Associated with heterotaxy, visceral, 12, autosomal.

What condition is associated with CIROP p.Gly180Arg (c.538G>C)?

CIROP p.Gly180Arg (c.538G>C) is associated with heterotaxy, visceral, 12, autosomal (ClinVar).

How common is CIROP p.Gly180Arg (c.538G>C) in the general population?

CIROP p.Gly180Arg (c.538G>C) is very rare (popmax 0.00026%, nfe) (gnomAD).

What do computational predictors say about CIROP p.Gly180Arg (c.538G>C)?

AlphaMissense predicts likely pathogenic (score 0.6142) — an in-silico prediction, not a clinical call.

CIROP p.Gly180Arg

c.538G>C · rs1266315800 · VCV1804115

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6142 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00026%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Conditions

heterotaxy, visceral, 12, autosomal

Computational evidence

Protein change
AlphaMissense	0.6142	likely pathogenic
SaProt	LLR -13.76	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.77	unconstrained · MANE · 5,635 bp · p 1.3e-32 · regional, not allelic
Overall
CADD	19.54	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00026% European (non-Finnish) · 1/385,006 alleles

Overall 0.000657% 1/152,192 alleles · very rare

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.Gly180Arg
Coding: c.538G>C
MANE Select: NM_001354640
dbSNP: rs1266315800
Type: single nucleotide variant
Location: chr14:23103740 (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.Arg22Ter Conflicting classifications of pathogenicity ★ 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-gly180arg (accessed [today's date]).

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