# NM_001170795.4(ATRAID):c.25C>T (p.Leu9Phe)

https://sugi.bio/variant/atraid-p-leu9phe

## Summary

**ATRAID p.Leu9Phe (c.25C>T)** is classified **Uncertain significance** in ATRAID (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.0602); Ultra-rare (popmax 0.0178%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs185160026 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0178%, afr)

## For patients & families {#patients}

This is a change in the ATRAID 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 | [ATRAID](https://sugi.bio/atlas/gene/ATRAID/) |
| Protein change (HGVS p.) | p.Leu9Phe |
| Coding change (HGVS c.) | c.25C>T |
| MANE Select transcript | [NM_001170795](https://www.ncbi.nlm.nih.gov/nuccore/NM_001170795) |
| dbSNP | [rs185160026](https://www.ncbi.nlm.nih.gov/snp/rs185160026/) |
| Variant type | single nucleotide variant |
| Location | chr2:27212393-27212393 (GRCh38) |
| ClinVar | [VCV3132107](https://www.ncbi.nlm.nih.gov/clinvar/variation/3132107/) |

**All HGVS expressions:** `NC_000002.11:g.27435261C>T`, `NC_000002.12:g.27212393C>T`, `NG_046394.1:g.4C>T`, `NG_166390.1:g.279C>T`, `NM_001170795.4:c.25C>T`, `NM_016085.5:c.-290C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0602)
- REVEL 0.015 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.05 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -3.705, GERP -4.74 — fast-evolving / accelerated position
- CADD: **PHRED 1.307**. 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 1.08** across the covering region of the MANE Select transcript (27,212,369–27,216,945), spanning 4,576 bp. Chi-square p 0.19. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.22**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.22**.
- Population frequency (gnomAD v4.1): grpmax **0.0178%** (afr) · FAF95 0.0105% · FAF99 0.00831% · 13/73,096 in the highest group · 16/1,551,070 alleles overall — ultra-rare (popmax 0.0178%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0178% | 5,623 |
| European (non-Finnish) | 0.000262% | 382,409 |

*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}

**ATRAID** population constraint: LOEUF 1.235, pLI 1.0538e-08, missense-Z -0.40297. *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 87.31, 70% of residues very-high.

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

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


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

**Molecular function:** xenobiotic transmembrane transporter activity.

**Biological process:** xenobiotic transmembrane transport, regulation of gene expression, positive regulation of bone mineralization, negative regulation of osteoblast proliferation, negative regulation of protein catabolic process, positive regulation of osteoblast differentiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-30.

**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 | 2024-01-30 |

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

## Similar variants {#similar}

Related ATRAID variant pages (same residue, condition, or type): [ATRAID c.-117C>A](/variant/atraid-c-minus-117c-a), [ATRAID c.-123A>C](/variant/atraid-c-minus-123a-c), [ATRAID c.-155G>A](/variant/atraid-c-minus-155g-a), [ATRAID c.-161A>G](/variant/atraid-c-minus-161a-g), [ATRAID c.-24A>T](/variant/atraid-c-minus-24a-t), [ATRAID c.-38C>T](/variant/atraid-c-minus-38c-t), [ATRAID c.-44C>G](/variant/atraid-c-minus-44c-g), [ATRAID c.-71G>A](/variant/atraid-c-minus-71g-a).

### 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 3132107). 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.*