# NM_000210.4(ITGA6):c.2422G>A (p.Val808Met)

https://sugi.bio/variant/itga6-p-val808met

## Summary

**ITGA6 p.Val808Met (c.2422G>A)** is classified **Uncertain significance** in ITGA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). AlphaMissense: ambiguous (0.4926); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ITGA6 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 | [ITGA6](https://sugi.bio/atlas/gene/ITGA6/) |
| Protein change (HGVS p.) | p.Val808Met |
| Coding change (HGVS c.) | c.2422G>A |
| MANE Select transcript | [NM_000210](https://www.ncbi.nlm.nih.gov/nuccore/NM_000210) |
| Variant type | single nucleotide variant |
| Location | chr2:172488145-172488145 (GRCh38) |
| ClinVar | [VCV4039961](https://www.ncbi.nlm.nih.gov/clinvar/variation/4039961/) |

**All HGVS expressions:** `NC_000002.11:g.173352873G>A`, `NC_000002.12:g.172488145G>A`, `NG_008853.1:g.65560G>A`, `NM_000210.4:c.2422G>A`, `NM_001079818.3:c.2422G>A`, `NM_001316306.2:c.2065G>A`, `NM_001365529.2:c.2422G>A`, `NM_001365530.2:c.2422G>A`, `NM_001394928.1:c.2539G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4926) — no call either way
- REVEL 0.353 (indeterminate)
- SaProt LLR -8.159 (tolerated)
- SpliceAI predicts **acceptor loss** (Δ 0.38) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.642, GERP 1.67, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **V847M** vs ClinVar **V808M**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 27.7**. 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 0.86** across the covering region of the MANE Select transcript (172,479,679–172,501,876), spanning 22,197 bp. Chi-square p 0.00022. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.38**, 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.*
- 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}

**ITGA6** population constraint: LOEUF 0.52, pLI 0.6874, missense-Z 2.5966. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.05, 43% of residues very-high.

**2 experimental structure(s)** (PDB): [7CEB](https://www.rcsb.org/structure/7CEB), [7CEC](https://www.rcsb.org/structure/7CEC).

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

*Describes the biological roles of ITGA6 (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:** ITGA6's established molecular role includes insulin-like growth factor I binding.


### Pathways affected {#pathways}

ITGA6 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Basigin interactions](https://reactome.org/content/detail/R-HSA-210991) | curated |
| [Developmental Lineage of Mammary Gland Alveolar Cells](https://reactome.org/content/detail/R-HSA-9927426) | 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 |
| [Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin](https://reactome.org/content/detail/R-HSA-9725554) | curated |
| [Syndecan interactions](https://reactome.org/content/detail/R-HSA-3000170) | curated |
| [Type I hemidesmosome assembly](https://reactome.org/content/detail/R-HSA-446107) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | electronic |
| [Laminin interactions](https://reactome.org/content/detail/R-HSA-3000157) | electronic |

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

**Molecular function:** insulin-like growth factor I binding, neuregulin binding, cadherin binding.

**Biological process:** cell-matrix adhesion, ectodermal cell differentiation, positive regulation of cell migration, cell-substrate adhesion, nail development, positive regulation of apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-23.

**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 | 2025-05-23 |

## 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 ITGA6 variant pages (same residue, condition, or type): [ITGA6 p.Ala1024Thr](/variant/itga6-p-ala1024thr), [ITGA6 p.Ala491Val](/variant/itga6-p-ala491val), [ITGA6 p.Ala90Thr](/variant/itga6-p-ala90thr), [ITGA6 p.Arg19Trp](/variant/itga6-p-arg19trp), [ITGA6 p.Arg484His](/variant/itga6-p-arg484his), [ITGA6 p.Arg578His](/variant/itga6-p-arg578his), [ITGA6 p.Arg902Gln](/variant/itga6-p-arg902gln), [ITGA6 p.Arg913Gly](/variant/itga6-p-arg913gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4039961). 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.*