# NM_201253.3(CRB1):c.2103C>G (p.Pro701=)

https://sugi.bio/variant/crb1-p-pro701

## Summary

**CRB1 p.Pro701= (c.2103C>G)** is classified **Conflicting classifications of pathogenicity** in CRB1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-25). Rare (popmax 0.19%, nfe); Associated with pigmented paravenous retinochoroidal atrophy.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs144436610 · 8 submitters · 5 linked conditions · rare (popmax 0.19%, nfe)

## For patients & families {#patients}

This is a change in the CRB1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to pigmented paravenous retinochoroidal atrophy.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | CRB1 is a diagnostic-grade gene on 3 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017208/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CRB1](https://sugi.bio/atlas/gene/CRB1/) |
| Protein change (HGVS p.) | p.Pro701= |
| Coding change (HGVS c.) | c.2103C>G |
| MANE Select transcript | [NM_201253](https://www.ncbi.nlm.nih.gov/nuccore/NM_201253) |
| dbSNP | [rs144436610](https://www.ncbi.nlm.nih.gov/snp/rs144436610/) |
| Variant type | single nucleotide variant |
| Location | chr1:197421931-197421931 (GRCh38) |
| ClinVar | [VCV289997](https://www.ncbi.nlm.nih.gov/clinvar/variation/289997/) |

**All HGVS expressions:** `NC_000001.10:g.197391061C>G`, `NC_000001.11:g.197421931C>G`, `NG_008483.2:g.225470C>G`, `NM_001193640.2:c.1767C>G`, `NM_001257965.2:c.1896C>G`, `NM_001257966.2:c.2103C>G`, `NM_201253.3:c.2103C>G`, `NR_047563.2:n.2056C>G`, `NR_047564.2:n.2264C>G`

## 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 -1.615, GERP -1.91 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.056**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.19%** (nfe) · FAF95 0.184% · FAF99 0.181% · 2,245/1,180,028 in the highest group · 2,583/1,614,096 alleles overall — rare (popmax 0.19%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.439% | 228 |
| European (non-Finnish) (grpmax) | 0.19% | 526 |
| Remaining individuals (not grpmax-eligible) | 0.158% | 631 |
| Middle Eastern | 0.115% | 866 |
| African / African-American | 0.0386% | 2,588 |
| South Asian | 0.0373% | 2,679 |
| Admixed American | 0.035% | 2,858 |
| Finnish (not grpmax-eligible) | 0.0282% | 3,552 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. 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.

*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}

**CRB1** population constraint: LOEUF 0.776, pLI 9.3619e-17, missense-Z 0.63626. *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):

- **inherited retinal dystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **701** lies in a UniProt-annotated variant site (in lca8); the egf-like 12 domain; a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 75.19, 14% of residues very-high.

**1 experimental structure(s)** (PDB): [4UU5](https://www.rcsb.org/structure/4UU5).

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-25.

**Submitter consensus:** conflicting (5 Likely benign, 3 Uncertain significance, 2 Benign).

**Submission history:** 10 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2019-10-22 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-28 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-18 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-09-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-25 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-11 |

## Associated conditions {#conditions}

[pigmented paravenous retinochoroidal atrophy](https://sugi.bio/atlas/disease/pigmented-paravenous-retinochoroidal-atrophy/), [retinitis pigmentosa 12](https://sugi.bio/atlas/disease/retinitis-pigmentosa-12/), [Leber congenital amaurosis 8](https://sugi.bio/atlas/disease/leber-congenital-amaurosis-8/), [Leber congenital amaurosis](https://sugi.bio/atlas/disease/leber-congenital-amaurosis/), [retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/).

**Reported phenotype names (ClinVar):** Pigmented paravenous retinochoroidal atrophy, Leber congenital amaurosis 8, Retinitis pigmentosa, not provided, Retinitis pigmentosa 12, Leber congenital amaurosis, not specified, RP WITH OR WITHOUT PPRPE, RP WITH OR WITHOUT PRESERVED PARAARTERIOLE RETINAL PIGMENT EPITHELIUM, RETINITIS PIGMENTOSA WITH OR WITHOUT PARAARTERIOLAR PRESERVATION OF RETINAL PIGMENT EPITHELIUM.

## Same-residue context {#hotspot}

Residue **701** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CRB1 p.Pro701fs](/variant/crb1-p-pro701fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CRB1 variant pages (same residue, condition, or type): [CRB1 p.Pro701fs](/variant/crb1-p-pro701fs), [CRB1 c.1172-2A>G](/variant/crb1-c-1172-minus-2a-g), [CRB1 c.2128+1G>C](/variant/crb1-c-2128-plus-1g-c), [CRB1 c.2129-1G>A](/variant/crb1-c-2129-minus-1g-a), [CRB1 c.2129-1G>C](/variant/crb1-c-2129-minus-1g-c), [CRB1 c.2129-2A>G](/variant/crb1-c-2129-minus-2a-g), [CRB1 c.2676+1G>A](/variant/crb1-c-2676-plus-1g-a), [CRB1 c.2676+1G>T](/variant/crb1-c-2676-plus-1g-t).

### 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 289997). 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.*