# NM_001029883.3(PCARE):c.3708del (p.Ser1237fs)

https://sugi.bio/variant/pcare-p-ser1237fs

## Summary

**PCARE p.Ser1237fs (c.3708del)** is classified **Uncertain significance** in PCARE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-08). Very rare (popmax 0.004%, nfe).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs756746994 · 2 submitters · very rare (popmax 0.004%, nfe)

## For patients & families {#patients}

This is a change in the PCARE gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PCARE](https://sugi.bio/atlas/gene/PCARE/) |
| Protein change (HGVS p.) | p.Ser1237fs |
| Coding change (HGVS c.) | c.3708del |
| MANE Select transcript | [NM_001029883](https://www.ncbi.nlm.nih.gov/nuccore/NM_001029883) |
| dbSNP | [rs756746994](https://www.ncbi.nlm.nih.gov/snp/rs756746994/) |
| Variant type | Deletion |
| Location | chr2:29065028-29065028 (GRCh38) |
| ClinVar | [VCV1040843](https://www.ncbi.nlm.nih.gov/clinvar/variation/1040843/) |

**All HGVS expressions:** `NC_000002.11:g.29287897del`, `NC_000002.12:g.29065031del`, `NG_021427.1:g.14234del`, `NM_001029883.3:c.3708del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.433, GERP -0.661, phastCons 0.997 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.032, pLI 1.0025e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 24.9**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.004%** (nfe) · FAF95 0.00307% · FAF99 0.00274% · 46/1,149,194 in the highest group · 49/1,554,788 alleles overall — very rare (popmax 0.004%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.004% | 24,982 |
| Remaining individuals (not grpmax-eligible) | 0.00332% | 30,133 |
| African / African-American | 0.00137% | 72,984 |

*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.*

## Gene constraint & dosage {#gene-context}

**PCARE** population constraint: LOEUF 1.032, pLI 1.0025e-21, missense-Z -1.1049; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **PCARE-related retinopathy** — Definitive (AR)

## Protein context {#protein}

Residue **1237** lies in the 'disordered' region; a UniProt-annotated variant site (found in a family with sensorineural hearing loss and retinal degeneration; likely pathogenic; the retinal involvement is more severe in double homozygotes also carrying a cep250 truncating variant).

AlphaFold model confidence (whole protein): pLDDT 44.15, 0% of residues very-high.

**1 experimental structure(s)** (PDB): [7LXF](https://www.rcsb.org/structure/7LXF).

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-05-08.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-08 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-16 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PCARE variant pages (same residue, condition, or type): [PCARE p.Ala628fs](/variant/pcare-p-ala628fs), [PCARE p.Arg767fs](/variant/pcare-p-arg767fs), [PCARE p.Asn316fs](/variant/pcare-p-asn316fs), [PCARE p.Gln410fs](/variant/pcare-p-gln410fs), [PCARE p.Glu1062fs](/variant/pcare-p-glu1062fs), [PCARE p.Gly570fs](/variant/pcare-p-gly570fs), [PCARE p.Gly964fs](/variant/pcare-p-gly964fs), [PCARE p.His395fs](/variant/pcare-p-his395fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1040843). 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.*