# NM_014945.5(ABLIM3):c.1345C>T (p.Arg449Trp)

https://sugi.bio/variant/ablim3-p-arg449trp

## Summary

**ABLIM3 p.Arg449Trp (c.1345C>T)** is classified **Uncertain significance** in ABLIM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: ambiguous (0.4456); Ultra-rare (popmax 0.0694%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs139404389 · 1 submitter · AlphaMissense ambiguous · ultra-rare (popmax 0.0694%, afr)

## For patients & families {#patients}

This is a change in the ABLIM3 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 | [ABLIM3](https://sugi.bio/atlas/gene/ABLIM3/) |
| Protein change (HGVS p.) | p.Arg449Trp |
| Coding change (HGVS c.) | c.1345C>T |
| MANE Select transcript | [NM_014945](https://www.ncbi.nlm.nih.gov/nuccore/NM_014945) |
| dbSNP | [rs139404389](https://www.ncbi.nlm.nih.gov/snp/rs139404389/) |
| Variant type | single nucleotide variant |
| Location | chr5:149242532-149242532 (GRCh38) |
| ClinVar | [VCV2591895](https://www.ncbi.nlm.nih.gov/clinvar/variation/2591895/) |

**All HGVS expressions:** `NC_000005.10:g.149242532C>T`, `NC_000005.9:g.148622095C>T`, `NG_051566.1:g.106086C>T`, `NM_001301015.3:c.1345C>T`, `NM_001301018.3:c.1246C>T`, `NM_001301028.3:c.1019-2349C>T`, `NM_001345858.2:c.1205-2349C>T`, `NM_001345859.2:c.1060C>T`, `NM_001345860.2:c.1019-2349C>T`, `NM_001345861.2:c.1060C>T`, `NM_001370417.1:c.1246C>T`, `NM_001370418.1:c.1019-2349C>T`, `NM_014945.5:c.1345C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4456) — no call either way
- REVEL 0.188 (benign-leaning)
- SaProt LLR -8.809 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- SpliceAI predicts **donor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.831, GERP 1.39, phastCons 0.986 — weakly conserved position
- CADD: **PHRED 29.4**. 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 0.89** across the covering region of the MANE Select transcript (149,142,096–149,258,401), spanning 116,305 bp. Chi-square p 0.0017. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.19**, donor loss **0.26**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 18 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 (gnomAD v4.1): grpmax **0.0694%** (afr) · FAF95 0.0543% · FAF99 0.049% · 52/74,884 in the highest group · 103/1,613,958 alleles overall — ultra-rare (popmax 0.0694%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0694% | 1,440 |
| South Asian | 0.00549% | 18,218 |
| Admixed American | 0.005% | 19,997 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,604 |
| European (non-Finnish) | 0.00331% | 30,257 |

*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}

**ABLIM3** population constraint: LOEUF 0.691, pLI 7.7214e-10, missense-Z 1.5617. *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 **449** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 61.31, 26% of residues very-high.

**2 experimental structure(s)** (PDB): [1UJS](https://www.rcsb.org/structure/1UJS), [2DJ7](https://www.rcsb.org/structure/2DJ7).

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

*Describes the biological roles of ABLIM3 (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.*


### Pathways affected {#pathways}

ABLIM3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | electronic |

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

**Biological process:** lamellipodium assembly, cilium assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-23.

**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 | 2025-06-23 |

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

## Similar variants {#similar}

Related ABLIM3 variant pages (same residue, condition, or type): [ABLIM3 p.Arg513Cys](/variant/ablim3-p-arg513cys), [ABLIM3 p.Ala166Gly](/variant/ablim3-p-ala166gly), [ABLIM3 p.Ala297Val](/variant/ablim3-p-ala297val), [ABLIM3 p.Ala371Asp](/variant/ablim3-p-ala371asp), [ABLIM3 p.Ala600Pro](/variant/ablim3-p-ala600pro), [ABLIM3 p.Arg15Trp](/variant/ablim3-p-arg15trp), [ABLIM3 p.Arg215Gln](/variant/ablim3-p-arg215gln), [ABLIM3 p.Arg238Cys](/variant/ablim3-p-arg238cys).

### 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 2591895). 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.*