# NM_020989.4(CRYGC):c.256G>T (p.Val86Phe)

https://sugi.bio/variant/crygc-p-val86phe

## Summary

**CRYGC p.Val86Phe (c.256G>T)** is classified **Likely benign** in CRYGC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-16). AlphaMissense: likely benign (0.1547); Rare (popmax 0.241%, afr); Associated with Nuclear pulverulent cataract.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs150910237 · 3 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.241%, afr)

## For patients & families {#patients}

This is a change in the CRYGC gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to Nuclear pulverulent cataract.

*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 | [CRYGC](https://sugi.bio/atlas/gene/CRYGC/) |
| Protein change (HGVS p.) | p.Val86Phe |
| Coding change (HGVS c.) | c.256G>T |
| MANE Select transcript | [NM_020989](https://www.ncbi.nlm.nih.gov/nuccore/NM_020989) |
| dbSNP | [rs150910237](https://www.ncbi.nlm.nih.gov/snp/rs150910237/) |
| Variant type | single nucleotide variant |
| Location | chr2:208128472-208128472 (GRCh38) |
| ClinVar | [VCV465773](https://www.ncbi.nlm.nih.gov/clinvar/variation/465773/) |

**All HGVS expressions:** `NC_000002.11:g.208993196C>A`, `NC_000002.12:g.208128472C>A`, `NG_008038.1:g.6359G>T`, `NG_008039.1:g.1118G>T`, `NM_020989.4:c.256G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1547)
- REVEL 0.192 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.937 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.59) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.039, GERP -4.81 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 17.07**. 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 1.00** across the covering region of the MANE Select transcript (208,128,206–208,129,792), spanning 1,586 bp. Chi-square p 0.96. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.59**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.59**, donor gain **0.00**.
- Pangolin: Δ**0.60** (gain), gain 0.60 / loss 0.29. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.241%** (afr) · FAF95 0.212% · FAF99 0.201% · 181/75,048 in the highest group · 215/1,614,198 alleles overall — rare (popmax 0.241%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.241% | 415 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,125 |
| Admixed American | 0.0167% | 6,003 |
| Middle Eastern | 0.0165% | 6,060 |
| South Asian | 0.0022% | 45,541 |
| European (non-Finnish) | 8.47e-05% | 1,180,040 |

*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}

**CRYGC** population constraint: LOEUF 0.941, pLI 0.0018396, missense-Z 0.24242; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **86** lies in the 'connecting peptide' region.

AlphaFold model confidence (whole protein): pLDDT 96.66, 97% of residues very-high.

**1 experimental structure(s)** (PDB): [2NBR](https://www.rcsb.org/structure/2NBR).

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-16.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-16 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-07-11 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-14 |

## Associated conditions {#conditions}

[Nuclear pulverulent cataract](https://sugi.bio/atlas/disease/nuclear-pulverulent-cataract/).

**Reported phenotype names (ClinVar):** Nuclear pulverulent cataract, CRYGC-related disorder, not specified, CRYGC-related condition, AllHighlyPenetrant.

## Similar variants {#similar}

Related CRYGC variant pages (same residue, condition, or type): [CRYGC p.Val86=](/variant/crygc-p-val86), [CRYGC p.Arg122His](/variant/crygc-p-arg122his), [CRYGC p.Arg15His](/variant/crygc-p-arg15his), [CRYGC p.Arg77Cys](/variant/crygc-p-arg77cys), [CRYGC p.Glu150Asp](/variant/crygc-p-glu150asp), [CRYGC p.Pro49Thr](/variant/crygc-p-pro49thr), [CRYGC c.10-10T>C](/variant/crygc-c-10-minus-10t-c), [CRYGC p.Gly41=](/variant/crygc-p-gly41).

### 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 465773). 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.*