# NM_000610.4(CD44):c.1250A>G (p.Lys417Arg)

https://sugi.bio/variant/cd44-p-lys417arg

## Summary

**CD44 p.Lys417Arg (c.1250A>G)** is classified **Benign** in CD44 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-16). AlphaMissense: likely benign (0.069); Common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with CD44-related disorder.

**At a glance:** Benign · review: No assertion criteria · rsID rs9666607 · 1 submitter · 1 linked condition · AlphaMissense likely benign · common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CD44 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to CD44-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 | [CD44](https://sugi.bio/atlas/gene/CD44/) |
| Protein change (HGVS p.) | p.Lys417Arg |
| Coding change (HGVS c.) | c.1250A>G |
| MANE Select transcript | [NM_000610](https://www.ncbi.nlm.nih.gov/nuccore/NM_000610) |
| dbSNP | [rs9666607](https://www.ncbi.nlm.nih.gov/snp/rs9666607/) |
| Variant type | single nucleotide variant |
| Location | chr11:35204608-35204608 (GRCh38) |
| ClinVar | [VCV3059515](https://www.ncbi.nlm.nih.gov/clinvar/variation/3059515/) |

**All HGVS expressions:** `LRG_815:g.70739A>G`, `LRG_815t1:c.668-10244A>G`, `LRG_815t2:c.1250A>G`, `NC_000011.10:g.35204608A>G`, `NC_000011.9:g.35226155A>G`, `NG_008937.1:g.70739A>G`, `NM_000610.4:c.1250A>G`, `NM_001001389.2:c.1121A>G`, `NM_001001390.2:c.668-3497A>G`, `NM_001001391.2:c.668-10244A>G`, `NM_001001392.2:c.234-17097A>G`, `NM_001202555.2:c.668-6638A>G`, `NM_001202556.2:c.667+14543A>G`, `NM_001202557.2:c.668-10244A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.069)
- REVEL 0.028 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.799 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.04, GERP -4.45, phastCons 0.08 — weakly conserved position
- CADD: **PHRED 4.054**. 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 1.07** across the covering region of the MANE Select transcript (35,196,831–35,229,330), spanning 32,499 bp. Chi-square p 0.099. 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 (A>T, 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 **94.1%** (eas) · FAF95 93.3% · FAF99 93% · 42,193/44,846 in the highest group · 1,144,256/1,611,714 alleles overall — common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 94.1% | 1 |
| African / African-American | 88.1% | 1 |
| South Asian | 82.1% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 76.8% | 1 |
| Finnish (not grpmax-eligible) | 73.2% | 1 |
| Remaining individuals (not grpmax-eligible) | 72.1% | 1 |
| Middle Eastern | 71.3% | 1 |
| Admixed American | 68.9% | 1 |
| European (non-Finnish) | 68% | 1 |
| Amish (not grpmax-eligible) | 65.5% | 2 |

*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}

**CD44** population constraint: LOEUF 0.654, pLI 0.0016068, missense-Z 0.90454. *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 **417** lies in a UniProt-annotated variant site (in); the 'stem' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 53.31, 21% of residues very-high.

**7 experimental structure(s)** (PDB): [1POZ](https://www.rcsb.org/structure/1POZ), [1UUH](https://www.rcsb.org/structure/1UUH), [2I83](https://www.rcsb.org/structure/2I83), [32NZ](https://www.rcsb.org/structure/32NZ), [4PZ3](https://www.rcsb.org/structure/4PZ3), [4PZ4](https://www.rcsb.org/structure/4PZ4).

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

*Describes the biological roles of CD44 (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:** CD44's established molecular role includes hyaluronic acid binding. p.Lys417Arg falls in the stem region.


### Pathways affected {#pathways}

CD44 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |
| [Developmental Lineage of Mammary Gland Luminal Epithelial Cells](https://reactome.org/content/detail/R-HSA-9927418) | curated |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |
| [Developmental Lineage of Mammary Stem Cells](https://reactome.org/content/detail/R-HSA-9938206) | curated |
| [Hyaluronan degradation](https://reactome.org/content/detail/R-HSA-2160916) | curated |
| [Hyaluronan metabolism](https://reactome.org/content/detail/R-HSA-2142845) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** hyaluronic acid binding, signaling receptor activity, cargo receptor activity.

**Biological process:** endocytosis, cell adhesion, cell migration, hyaluronan catabolic process, positive regulation of heterotypic cell-cell adhesion, T cell activation.

## Clinical significance {#significance}

**Benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-10-16.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-10-16 |

## Associated conditions {#conditions}

[CD44-related disorder](https://sugi.bio/atlas/disease/cd44-related-disorder/).

**Reported phenotype names (ClinVar):** CD44-related disorder, CD44-related condition.

## Similar variants {#similar}

Related CD44 variant pages (same residue, condition, or type): [CD44 c.1282+10G>A](/variant/cd44-c-1282-plus-10g-a), [CD44 c.*1C>G](/variant/cd44-c-star-1c-g), [CD44 p.Arg46Gln](/variant/cd44-p-arg46gln), [CD44 p.Asp243=](/variant/cd44-p-asp243), [CD44 p.Glu374=](/variant/cd44-p-glu374), [CD44 p.Ile479Thr](/variant/cd44-p-ile479thr), [CD44 p.Thr216=](/variant/cd44-p-thr216), [CD44 c.367+7T>C](/variant/cd44-c-367-plus-7t-c).

### 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 3059515). 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.*