# NM_004517.4(ILK):c.1041T>C (p.Pro347=)

https://sugi.bio/variant/ilk-p-pro347

## Summary

**ILK p.Pro347= (c.1041T>C)** is classified **Likely benign** in ILK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-06). Ultra-rare (popmax 0.0176%, sas); Associated with familial hypertrophic cardiomyopathy.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs748450237 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0176%, sas)

## For patients & families {#patients}

This is a change in the ILK gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to familial hypertrophic cardiomyopathy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ILK](https://sugi.bio/atlas/gene/ILK/) |
| Protein change (HGVS p.) | p.Pro347= |
| Coding change (HGVS c.) | c.1041T>C |
| MANE Select transcript | [NM_004517](https://www.ncbi.nlm.nih.gov/nuccore/NM_004517) |
| dbSNP | [rs748450237](https://www.ncbi.nlm.nih.gov/snp/rs748450237/) |
| Variant type | single nucleotide variant |
| Location | chr11:6609998-6609998 (GRCh38) |
| ClinVar | [VCV1553194](https://www.ncbi.nlm.nih.gov/clinvar/variation/1553194/) |

**All HGVS expressions:** `LRG_444:g.11266T>C`, `LRG_444t1:c.1041T>C`, `NC_000011.10:g.6609998T>C`, `NC_000011.9:g.6631229T>C`, `NG_029702.1:g.11266T>C`, `NM_001014794.3:c.1041T>C`, `NM_001014795.3:c.1041T>C`, `NM_001278441.2:c.858T>C`, `NM_001278442.2:c.639T>C`, `NM_004517.4:c.1041T>C`, `NM_006284.4:c.*924A>G`

## 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 -3.46, GERP -1.71 — fast-evolving / accelerated position
- CADD: **PHRED 11.72**. 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>A, Δ0.66 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 **0.0176%** (sas) · FAF95 0.011% · FAF99 0.00898% · 16/91,082 in the highest group · 17/1,614,102 alleles overall — ultra-rare (popmax 0.0176%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0176% | 5,693 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |

*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}

**ILK** population constraint: LOEUF 0.798, pLI 1.6191e-07, missense-Z 1.4078. *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):

- **dilated cardiomyopathy** — Limited (AD)

## Protein context {#protein}

Residue **347** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 88.13, 62% of residues very-high.

**17 experimental structure(s)** (PDB): [2KBX](https://www.rcsb.org/structure/2KBX), [3F6Q](https://www.rcsb.org/structure/3F6Q), [3IXE](https://www.rcsb.org/structure/3IXE), [3KMU](https://www.rcsb.org/structure/3KMU), [3KMW](https://www.rcsb.org/structure/3KMW), [3REP](https://www.rcsb.org/structure/3REP) — incl. mutant structure 6MIB.

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

*Describes the biological roles of ILK (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:** ILK's established molecular role includes magnesium ion binding. p.Pro347= falls in the protein kinase domain.


### Pathways affected {#pathways}

ILK participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell-extracellular matrix interactions](https://reactome.org/content/detail/R-HSA-446353) | curated |
| [Localization of the PINCH-ILK-PARVIN complex to focal adhesions](https://reactome.org/content/detail/R-HSA-446343) | curated |

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

**Molecular function:** magnesium ion binding, integrin binding, ATP binding, protein kinase binding.

**Biological process:** cell morphogenesis, mitotic spindle organization, integrin-mediated signaling pathway, positive regulation of signal transduction, tumor necrosis factor-mediated signaling pathway, substrate adhesion-dependent cell spreading.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-12-06.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-06 |

## Associated conditions {#conditions}

[familial hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/familial-hypertrophic-cardiomyopathy/).

**Reported phenotype names (ClinVar):** Primary familial hypertrophic cardiomyopathy, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ILK variant pages (same residue, condition, or type): [ILK p.Ala41Val](/variant/ilk-p-ala41val), [ILK p.Arg149Gln](/variant/ilk-p-arg149gln), [ILK p.Arg161Cys](/variant/ilk-p-arg161cys), [ILK p.Arg161His](/variant/ilk-p-arg161his), [ILK p.Arg334Gln](/variant/ilk-p-arg334gln), [ILK p.Arg436Gln](/variant/ilk-p-arg436gln), [ILK p.Arg46Cys](/variant/ilk-p-arg46cys), [ILK p.Arg59Trp](/variant/ilk-p-arg59trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1553194). 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.*