# NM_001354587.1(ANKRD36):c.1584C>T (p.Pro528=)

https://sugi.bio/variant/ankrd36-p-pro528

## Summary

**ANKRD36 p.Pro528= (c.1584C>T)** is classified **Likely benign** in ANKRD36 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-01). No allele count reported in gnomAD v4.1 (AN 1,536,960).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · no allele count reported in gnomAD v4.1 (AN 1,536,960)

## For patients & families {#patients}

This is a change in the ANKRD36 gene that is classified as likely benign — not considered disease-causing, 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 | [ANKRD36](https://sugi.bio/atlas/gene/ANKRD36/) |
| Protein change (HGVS p.) | p.Pro528= |
| Coding change (HGVS c.) | c.1584C>T |
| MANE Select transcript | [NM_001354587](https://www.ncbi.nlm.nih.gov/nuccore/NM_001354587) |
| Variant type | single nucleotide variant |
| Location | chr2:97167718-97167718 (GRCh38) |
| ClinVar | [VCV3778088](https://www.ncbi.nlm.nih.gov/clinvar/variation/3778088/) |

**All HGVS expressions:** `NC_000002.11:g.97833455C>T`, `NC_000002.12:g.97167718C>T`, `NM_001354587.1:c.1584C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.238 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.14**. 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 deltas (raw): acceptor loss **0.18**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 49 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,536,960)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ANKRD36** population constraint: LOEUF 1.132, pLI 3.9648e-55, missense-Z 0.77497. *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 **528** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 50.82, 8% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-01 |

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

## Similar variants {#similar}

Related ANKRD36 variant pages (same residue, condition, or type): [ANKRD36 c.2173-3A>C](/variant/ankrd36-c-2173-minus-3a-c), [ANKRD36 c.-4G>C](/variant/ankrd36-c-minus-4g-c), [ANKRD36 p.Ala228=](/variant/ankrd36-p-ala228), [ANKRD36 p.Asp404=](/variant/ankrd36-p-asp404), [ANKRD36 p.Asp558=](/variant/ankrd36-p-asp558), [ANKRD36 p.Cys1792=](/variant/ankrd36-p-cys1792), [ANKRD36 p.Cys445=](/variant/ankrd36-p-cys445), [ANKRD36 p.Gly1189=](/variant/ankrd36-p-gly1189).

### 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 3778088). 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.*