# NM_001378068.1(ANKAR):c.3325T>C (p.Cys1109Arg)

https://sugi.bio/variant/ankar-p-cys1109arg

## Summary

**ANKAR p.Cys1109Arg (c.3325T>C)** is classified **Uncertain significance** in ANKAR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.8362); Very rare (popmax 0.0017%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2468535202 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.0017%, amr)

## For patients & families {#patients}

This is a change in the ANKAR 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 | [ANKAR](https://sugi.bio/atlas/gene/ANKAR/) |
| Protein change (HGVS p.) | p.Cys1109Arg |
| Coding change (HGVS c.) | c.3325T>C |
| MANE Select transcript | [NM_001378068](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378068) |
| dbSNP | [rs2468535202](https://www.ncbi.nlm.nih.gov/snp/rs2468535202/) |
| Variant type | single nucleotide variant |
| Location | chr2:189733131-189733131 (GRCh38) |
| ClinVar | [VCV3120259](https://www.ncbi.nlm.nih.gov/clinvar/variation/3120259/) |

**All HGVS expressions:** `NC_000002.11:g.190597857T>C`, `NC_000002.12:g.189733131T>C`, `NM_001378068.1:c.3325T>C`, `NM_144708.3:c.3325T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8362)
- REVEL 0.755 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.456 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 5.983, GERP 1.9, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.6**. 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 0.93** across the covering region of the MANE Select transcript (189,676,491–189,746,624), spanning 70,133 bp. Chi-square p 0.0059. 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 (T>G, Δ0.74 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 **0.0017%** (amr) · FAF95 0.000765% · FAF99 0.000606% · 1/58,904 in the highest group · 17/1,455,744 alleles overall — very rare (popmax 0.0017%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0017% | 58,904 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,316 |
| European (non-Finnish) | 0.00127% | 78,531 |

*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}

**ANKAR** population constraint: LOEUF 1.07, pLI 5.6721e-33, missense-Z 1.2618. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.79, 53% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-28.

**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 | 2024-02-28 |

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

## Similar variants {#similar}

Related ANKAR variant pages (same residue, condition, or type): [ANKAR p.Asn938=](/variant/ankar-p-asn938), [ANKAR p.Gln1419Leu](/variant/ankar-p-gln1419leu), [ANKAR p.Ile1349=](/variant/ankar-p-ile1349), [ANKAR p.Leu94Arg](/variant/ankar-p-leu94arg), [ANKAR p.Thr206Ala](/variant/ankar-p-thr206ala), [ANKAR p.Thr92=](/variant/ankar-p-thr92), [ANKAR p.Tyr1262Ser](/variant/ankar-p-tyr1262ser), [ANKAR p.Val776Ala](/variant/ankar-p-val776ala).

### 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 3120259). 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.*