# NM_001354640.2(CIROP):c.1151C>T (p.Ser384Leu)

https://sugi.bio/variant/cirop-p-ser384leu

## Summary

**CIROP p.Ser384Leu (c.1151C>T)** is classified **Pathogenic** in CIROP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-03-15). AlphaMissense: ambiguous (0.4279); Very rare (popmax 0.00349%, afr); Associated with heterotaxy, visceral, 12, autosomal.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs183023758 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00349%, afr)

## For patients & families {#patients}

This is a change in the CIROP gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to heterotaxy, visceral, 12, autosomal.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026669/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CIROP](https://sugi.bio/atlas/gene/CIROP/) |
| Protein change (HGVS p.) | p.Ser384Leu |
| Coding change (HGVS c.) | c.1151C>T |
| MANE Select transcript | [NM_001354640](https://www.ncbi.nlm.nih.gov/nuccore/NM_001354640) |
| dbSNP | [rs183023758](https://www.ncbi.nlm.nih.gov/snp/rs183023758/) |
| Variant type | single nucleotide variant |
| Location | chr14:23102250-23102250 (GRCh38) |
| ClinVar | [VCV1344488](https://www.ncbi.nlm.nih.gov/clinvar/variation/1344488/) |

**All HGVS expressions:** `NC_000014.8:g.23571459G>A`, `NC_000014.9:g.23102250G>A`, `NM_001354640.2:c.1151C>T`, `NM_001402427.1:c.986C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4279) — no call either way
- SaProt LLR -12.18 (damaging)
- Conservation: phyloP 5.091, GERP 2.03, phastCons 1 — highly conserved
- CADD: **PHRED 24.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.77** across the covering region of the MANE Select transcript (23,099,285–23,104,920), spanning 5,635 bp. Chi-square p 1.3e-32. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.25 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00349%** (afr) · FAF95 0.00153% · FAF99 0.00122% · 2/57,374 in the highest group · 14/702,964 alleles overall — very rare (popmax 0.00349%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00349% | 28,687 |
| European (non-Finnish) | 0.00286% | 34,997 |
| East Asian | 0.00268% | 37,282 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Protein context {#protein}

Residue **384** lies in a UniProt-annotated variant site (in htx12); a UniProt-annotated variant site (in htx12; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 73.73, 35% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2022-03-15.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2022-03-15 |

## Associated conditions {#conditions}

[heterotaxy, visceral, 12, autosomal](https://sugi.bio/atlas/disease/heterotaxy-visceral-12-autosomal/).

**Reported phenotype names (ClinVar):** Heterotaxy, visceral, 12, autosomal.

## Similar variants {#similar}

Related CIROP variant pages (same residue, condition, or type): [CIROP p.Gln528Ter](/variant/cirop-p-gln528ter), [CIROP p.Arg22Ter](/variant/cirop-p-arg22ter), [CIROP p.Gly180Arg](/variant/cirop-p-gly180arg), [CIROP p.Gly511Glu](/variant/cirop-p-gly511glu), [CIROP p.Ser31Phe](/variant/cirop-p-ser31phe), [CIROP p.Tyr68Cys](/variant/cirop-p-tyr68cys), [CIROP p.Arg191Ter](/variant/cirop-p-arg191ter), [CIROP p.Arg389Ile](/variant/cirop-p-arg389ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1344488). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*