# NM_001201427.2(DAAM2):c.484C>T (p.Arg162Trp)

https://sugi.bio/variant/daam2-p-arg162trp

## Summary

**DAAM2 p.Arg162Trp (c.484C>T)** is classified **Uncertain significance** in DAAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.2252); Very rare (popmax 0.00988%, sas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00988%, sas)

## For patients & families {#patients}

This is a change in the DAAM2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [DAAM2](https://sugi.bio/atlas/gene/DAAM2/) |
| Protein change (HGVS p.) | p.Arg162Trp |
| Coding change (HGVS c.) | c.484C>T |
| MANE Select transcript | [NM_001201427](https://www.ncbi.nlm.nih.gov/nuccore/NM_001201427) |
| Variant type | single nucleotide variant |
| Location | chr6:39867565-39867565 (GRCh38) |
| ClinVar | [VCV4237287](https://www.ncbi.nlm.nih.gov/clinvar/variation/4237287/) |

**All HGVS expressions:** `NC_000006.11:g.39835341C>T`, `NC_000006.12:g.39867565C>T`, `NM_001201427.2:c.484C>T`, `NM_015345.4:c.484C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2252)
- REVEL 0.665 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.821 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 4.771, GERP -1.1, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 33.0**. 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 0.76** across the covering region of the MANE Select transcript (39,867,510–39,878,488), spanning 10,978 bp. Chi-square p 5e-07. 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 (C>A, Δ0.79 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 **0.00988%** (sas) · FAF95 0.00514% · FAF99 0.00375% · 9/91,088 in the highest group · 34/1,613,894 alleles overall — very rare (popmax 0.00988%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00988% | 10,121 |
| African / African-American | 0.00267% | 37,452 |
| European (non-Finnish) | 0.00178% | 56,186 |
| Admixed American | 0.00167% | 60,006 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,468 |

*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}

**DAAM2** population constraint: LOEUF 0.488, pLI 0.97715, missense-Z 0.8738. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **idiopathic multidrug-resistant nephrotic syndrome** — Limited (AR)

## Protein context {#protein}

Residue **162** lies in the gbd/fh3 domain.

AlphaFold model confidence (whole protein): pLDDT 80.02, 43% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-05.

**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 | 2025-08-05 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related DAAM2 variant pages (same residue, condition, or type): [DAAM2 p.Arg335Trp](/variant/daam2-p-arg335trp), [DAAM2 p.Arg676Trp](/variant/daam2-p-arg676trp), [DAAM2 p.Arg990Cys](/variant/daam2-p-arg990cys), [DAAM2 p.Gln760Arg](/variant/daam2-p-gln760arg), [DAAM2 p.Glu956Lys](/variant/daam2-p-glu956lys), [DAAM2 p.Ile699Val](/variant/daam2-p-ile699val), [DAAM2 p.Ala117Val](/variant/daam2-p-ala117val), [DAAM2 p.Ala167Thr](/variant/daam2-p-ala167thr).

### 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 4237287). 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.*