# NM_001270520.2(DAAM1):c.1668T>A (p.Pro556=)

https://sugi.bio/variant/daam1-p-pro556

## Summary

**DAAM1 p.Pro556= (c.1668T>A)** is classified **Likely benign** in DAAM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-29). Low-frequency (popmax 1.28%, eas); Associated with DAAM1-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs781426332 · 1 submitter · 1 linked condition · low-frequency (popmax 1.28%, eas)

## For patients & families {#patients}

This is a change in the DAAM1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to DAAM1-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 | [DAAM1](https://sugi.bio/atlas/gene/DAAM1/) |
| Protein change (HGVS p.) | p.Pro556= |
| Coding change (HGVS c.) | c.1668T>A |
| MANE Select transcript | [NM_001270520](https://www.ncbi.nlm.nih.gov/nuccore/NM_001270520) |
| dbSNP | [rs781426332](https://www.ncbi.nlm.nih.gov/snp/rs781426332/) |
| Variant type | single nucleotide variant |
| Location | chr14:59331316-59331316 (GRCh38) |
| ClinVar | [VCV3038460](https://www.ncbi.nlm.nih.gov/clinvar/variation/3038460/) |

**All HGVS expressions:** `NC_000014.8:g.59798034T>A`, `NC_000014.9:g.59331316T>A`, `NG_047127.1:g.147706T>A`, `NG_129172.1:g.399T>A`, `NM_001270520.2:c.1668T>A`, `NM_014992.2:c.1668T>A`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.262, GERP -2.37 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.468**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>C, Δ0.20 donor loss), 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 **1.28%** (eas) · FAF95 1.15% · FAF99 1.1% · 231/17,994 in the highest group · 2,771/1,083,420 alleles overall — low-frequency (popmax 1.28%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 1.28% | 78 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.749% | 134 |
| Remaining individuals (not grpmax-eligible) | 0.465% | 215 |
| Middle Eastern | 0.455% | 220 |
| Finnish (not grpmax-eligible) | 0.437% | 229 |
| Admixed American | 0.35% | 286 |
| African / African-American | 0.325% | 308 |
| Amish (not grpmax-eligible) | 0.222% | 450 |
| European (non-Finnish) | 0.214% | 468 |
| South Asian | 0.0735% | 1,360 |

*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}

**DAAM1** population constraint: LOEUF 0.509, pLI 0.53941, missense-Z 1.9445. *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 **556** lies in the fh1 domain; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 80.52, 46% of residues very-high.

**2 experimental structure(s)** (PDB): [2J1D](https://www.rcsb.org/structure/2J1D), [2Z6E](https://www.rcsb.org/structure/2Z6E).

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

*Describes the biological roles of DAAM1 (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}

DAAM1 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [PCP/CE pathway](https://reactome.org/content/detail/R-HSA-4086400) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-10-29.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-29 |

## Associated conditions {#conditions}

[DAAM1-related disorder](https://sugi.bio/atlas/disease/daam1-related-disorder/).

**Reported phenotype names (ClinVar):** DAAM1-related disorder, DAAM1-related condition.

## Similar variants {#similar}

Related DAAM1 variant pages (same residue, condition, or type): [DAAM1 p.Gly964Asp](/variant/daam1-p-gly964asp), [DAAM1 c.1373-6G>A](/variant/daam1-c-1373-minus-6g-a), [DAAM1 c.2694+8T>C](/variant/daam1-c-2694-plus-8t-c), [DAAM1 p.Ala509=](/variant/daam1-p-ala509), [DAAM1 p.Gln463=](/variant/daam1-p-gln463), [DAAM1 p.Gly8=](/variant/daam1-p-gly8), [DAAM1 p.Leu241=](/variant/daam1-p-leu241), [DAAM1 p.Lys186=](/variant/daam1-p-lys186).

### 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 3038460). 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.*