# NM_054027.6(ANKH):c.13C>A (p.Pro5Thr)

https://sugi.bio/variant/ankh-p-pro5thr

## Summary

**ANKH p.Pro5Thr (c.13C>A)** is classified **Pathogenic/Likely pathogenic** in ANKH (ClinVar, No assertion criteria, 2 submitters; last evaluated 2024-09-17). AlphaMissense: likely benign (0.2214); Very rare (popmax 0.000254%, nfe); Associated with ANKH-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: No assertion criteria · rsID rs121908410 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the ANKH gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to ANKH-related disorder.

*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 | [ANKH](https://sugi.bio/atlas/gene/ANKH/) |
| Protein change (HGVS p.) | p.Pro5Thr |
| Coding change (HGVS c.) | c.13C>A |
| MANE Select transcript | [NM_054027](https://www.ncbi.nlm.nih.gov/nuccore/NM_054027) |
| dbSNP | [rs121908410](https://www.ncbi.nlm.nih.gov/snp/rs121908410/) |
| Variant type | single nucleotide variant |
| Location | chr5:14871435-14871435 (GRCh38) |
| ClinVar | [VCV5199](https://www.ncbi.nlm.nih.gov/clinvar/variation/5199/) |

**All HGVS expressions:** `LRG_1362:g.5351C>A`, `LRG_1362t1:c.13C>A`, `NC_000005.10:g.14871435G>T`, `NC_000005.9:g.14871544G>T`, `NG_008273.2:g.5351C>A`, `NM_054027.4:c.13C>A`, `NM_054027.6:c.13C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.2214) — ⚠ discordant with the pathogenic call
- REVEL 0.65 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -7.221 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 11.089, GERP 1.66, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.9**. 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 0.61** across the covering region of the MANE Select transcript (14,711,281–14,871,447), spanning 160,166 bp. Chi-square p 1.1e-21. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,226 in the highest group · 3/1,460,586 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

**ANKH** population constraint: LOEUF 0.463, pLI 0.99706, missense-Z 3.5436; 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 **5** lies in a UniProt-annotated variant site (in ccal2).

AlphaFold model confidence (whole protein): pLDDT 84.57, 44% of residues very-high.

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

*Describes the biological roles of ANKH (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:** ANKH's established molecular role includes phosphate transmembrane transporter activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Miscellaneous transport and binding events](https://reactome.org/content/detail/R-HSA-5223345) | curated |

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

**Molecular function:** phosphate transmembrane transporter activity, ATP transmembrane transporter activity, transmembrane transporter activity.

**Biological process:** ATP export.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-09-17.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2003–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-09-17 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2003-09-01 |

## Associated conditions {#conditions}

[ANKH-related disorder](https://sugi.bio/atlas/disease/ankh-related-disorder/), [chondrocalcinosis 2](https://sugi.bio/atlas/disease/chondrocalcinosis-2/).

**Reported phenotype names (ClinVar):** ANKH-related disorder, Chondrocalcinosis 2, ANKH-Related Disorders, ANKH-related condition, Familial calcium pyrophosphate deposition, CALCIUM GOUT, CALCIUM PYROPHOSPHATE ARTHROPATHY.

## Same-residue context {#hotspot}

Residue **5** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ANKH p.Pro5Leu](/variant/ankh-p-pro5leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ANKH variant pages (same residue, condition, or type): [ANKH p.Pro5Leu](/variant/ankh-p-pro5leu), [ANKH p.Pro5Ser](/variant/ankh-p-pro5ser), [ANKH c.*3752G>A](/variant/ankh-c-star-3752g-a), [ANKH p.Ala448Thr](/variant/ankh-p-ala448thr), [ANKH p.Lys326Gln](/variant/ankh-p-lys326gln), [ANKH p.Val313Met](/variant/ankh-p-val313met), [ANKH c.1011+15T>G](/variant/ankh-c-1011-plus-15t-g), [ANKH c.1012-11T>G](/variant/ankh-c-1012-minus-11t-g).

### 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 5199). 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.*