# NM_001907.3(CTRL):c.602G>A (p.Cys201Tyr)

https://sugi.bio/variant/ctrl-p-cys201tyr

## Summary

**CTRL p.Cys201Tyr (c.602G>A)** is classified **Uncertain significance** in CTRL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.9944); Ultra-rare (popmax 0.0453%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs201073485 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0453%, afr)

## For patients & families {#patients}

This is a change in the CTRL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CTRL](https://sugi.bio/atlas/gene/CTRL/) |
| Protein change (HGVS p.) | p.Cys201Tyr |
| Coding change (HGVS c.) | c.602G>A |
| MANE Select transcript | [NM_001907](https://www.ncbi.nlm.nih.gov/nuccore/NM_001907) |
| dbSNP | [rs201073485](https://www.ncbi.nlm.nih.gov/snp/rs201073485/) |
| Variant type | single nucleotide variant |
| Location | chr16:67930216-67930216 (GRCh38) |
| ClinVar | [VCV2570460](https://www.ncbi.nlm.nih.gov/clinvar/variation/2570460/) |

**All HGVS expressions:** `NC_000016.10:g.67930216C>T`, `NC_000016.9:g.67964119C>T`, `NG_051639.1:g.6660G>A`, `NM_001907.3:c.602G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9944)
- REVEL 0.923 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.842 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 6, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in CTRL (of 1,541 modeled).
- CADD: **PHRED 25.8**. 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 0.95** across the covering region of the MANE Select transcript (67,929,937–67,931,852), spanning 1,915 bp. Chi-square p 0.39. 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 (C>A, Δ0.50 acceptor gain), 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 **0.0453%** (afr) · FAF95 0.0333% · FAF99 0.0291% · 34/75,030 in the highest group · 42/1,614,040 alleles overall — ultra-rare (popmax 0.0453%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0453% | 2,207 |
| Admixed American | 0.00333% | 30,008 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |
| European (non-Finnish) | 0.000339% | 295,006 |

*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}

**CTRL** population constraint: LOEUF 1.372, pLI 4.7747e-14, missense-Z 0.52126. *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 **201** lies in a disulfide bond; the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 91.26, 79% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CTRL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CTRL's established molecular role includes serine-type peptidase activity. p.Cys201Tyr falls in the peptidase s1 domain.


### Pathways affected {#pathways}

CTRL participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Developmental Lineage of Pancreatic Acinar Cells](https://reactome.org/content/detail/R-HSA-9925561) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** serine-type peptidase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-31.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-31 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CTRL variant pages (same residue, condition, or type): [CTRL p.Gly230Ser](/variant/ctrl-p-gly230ser), [CTRL p.Glu151Gln](/variant/ctrl-p-glu151gln), [CTRL p.Val70=](/variant/ctrl-p-val70), [CTRL p.Ala131Thr](/variant/ctrl-p-ala131thr), [CTRL p.Ala27Thr](/variant/ctrl-p-ala27thr), [CTRL p.Arg136His](/variant/ctrl-p-arg136his), [CTRL p.Arg162His](/variant/ctrl-p-arg162his), [CTRL p.Arg188Trp](/variant/ctrl-p-arg188trp).

### 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 2570460). 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.*