# NM_000632.4(ITGAM):c.1839G>T (p.Arg613Ser)

https://sugi.bio/variant/itgam-p-arg613ser

## Summary

**ITGAM p.Arg613Ser (c.1839G>T)** is classified **Uncertain significance** in ITGAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.7474); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ITGAM 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 | [ITGAM](https://sugi.bio/atlas/gene/ITGAM/) |
| Protein change (HGVS p.) | p.Arg613Ser |
| Coding change (HGVS c.) | c.1839G>T |
| MANE Select transcript | [NM_000632](https://www.ncbi.nlm.nih.gov/nuccore/NM_000632) |
| Variant type | single nucleotide variant |
| Location | chr16:31321464-31321464 (GRCh38) |
| ClinVar | [VCV4761426](https://www.ncbi.nlm.nih.gov/clinvar/variation/4761426/) |

**All HGVS expressions:** `LRG_1333:g.66498G>T`, `LRG_1333t1:c.1839G>T`, `NC_000016.10:g.31321464G>T`, `NC_000016.9:g.31332785G>T`, `NG_011719.1:g.66498G>T`, `NM_000632.4:c.1839G>T`, `NM_001145808.2:c.1842G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7474)
- REVEL 0.422 (indeterminate)
- SaProt LLR -9.061 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.611, GERP -1.61, phastCons 1 — weakly conserved position
- CADD: **PHRED 24.4**. 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 0.91** across the covering region of the MANE Select transcript (31,260,065–31,331,704), spanning 71,639 bp. Chi-square p 0.00026. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.26**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss at this position.
- 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.*
- Pangolin: Δ**0.36** (loss), gain 0.01 / loss 0.36. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ITGAM** population constraint: LOEUF 0.678, pLI 7.6195e-11, missense-Z 1.3471. *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 **613** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 86.30, 51% of residues very-high.

**31 experimental structure(s)** (PDB): [1BHO](https://www.rcsb.org/structure/1BHO), [1BHQ](https://www.rcsb.org/structure/1BHQ), [1IDN](https://www.rcsb.org/structure/1IDN), [1IDO](https://www.rcsb.org/structure/1IDO), [1JLM](https://www.rcsb.org/structure/1JLM), [1M1U](https://www.rcsb.org/structure/1M1U) — incl. mutant structure 1N9Z.

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

*Describes the biological roles of ITGAM (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:** ITGAM's established molecular role includes heat shock protein binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |
| [Differentiation of Circulating Monocytes](https://reactome.org/content/detail/R-HSA-9968734) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Toll Like Receptor 4 (TLR4) Cascade](https://reactome.org/content/detail/R-HSA-166016) | curated |

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

**Molecular function:** heat shock protein binding.

**Biological process:** cell-matrix adhesion, ectodermal cell differentiation, positive regulation of superoxide anion generation, cell-cell adhesion mediated by integrin, positive regulation of neutrophil degranulation, leukocyte adhesion to vascular endothelial cell.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ITGAM variant pages (same residue, condition, or type): [ITGAM c.704+5G>A](/variant/itgam-c-704-plus-5g-a), [ITGAM p.Ala31Thr](/variant/itgam-p-ala31thr), [ITGAM p.Ala433Val](/variant/itgam-p-ala433val), [ITGAM p.Ala753Val](/variant/itgam-p-ala753val), [ITGAM p.Ala943Val](/variant/itgam-p-ala943val), [ITGAM p.Arg1003His](/variant/itgam-p-arg1003his), [ITGAM p.Arg131Trp](/variant/itgam-p-arg131trp), [ITGAM p.Arg224Trp](/variant/itgam-p-arg224trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4761426). 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.*