# NM_213595.4(ISCU):c.19T>G (p.Phe7Val)

https://sugi.bio/variant/iscu-p-phe7val

## Summary

**ISCU p.Phe7Val (c.19T>G)** is classified **Benign/Likely benign** in ISCU (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.1508); Common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary myopathy with lactic acidosis due to ISCU deficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs10778647 · 6 submitters · 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 ISCU gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 submitters, and is linked to hereditary myopathy with lactic acidosis due to ISCU deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | ISCU is a diagnostic-grade gene on 11 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016643/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ISCU](https://sugi.bio/atlas/gene/ISCU/) |
| Protein change (HGVS p.) | p.Phe7Val |
| Coding change (HGVS c.) | c.19T>G |
| MANE Select transcript | [NM_213595](https://www.ncbi.nlm.nih.gov/nuccore/NM_213595) |
| dbSNP | [rs10778647](https://www.ncbi.nlm.nih.gov/snp/rs10778647/) |
| Variant type | single nucleotide variant |
| Location | chr12:108562641-108562641 (GRCh38) |
| ClinVar | [VCV768575](https://www.ncbi.nlm.nih.gov/clinvar/variation/768575/) |

**All HGVS expressions:** `LRG_1285:g.3749A>C`, `NC_000012.11:g.108956417T>G`, `NC_000012.12:g.108562641T>G`, `NG_011857.1:g.5124T>G`, `NG_012155.2:g.3749A>C`, `NM_001301140.1:c.19T>G`, `NM_001301141.1:c.19T>G`, `NM_001320042.1:c.19T>G`, `NM_014301.4:c.-153T>G`, `NM_213595.2:c.19T>G`, `NM_213595.4:c.19T>G`, `NR_135127.1:n.1179T>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** (0.1508)
- REVEL 0.204 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.049 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.993, GERP 0.854, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.97**. 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 1.10** across the covering region of the MANE Select transcript (108,562,623–108,568,913), spanning 6,290 bp. Chi-square p 0.16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for ISCU (272 scored positions, the nearest 22 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **94.1%** (eas) · FAF95 93.2% · FAF99 92.9% · 33,426/35,534 in the highest group · 1,286,091/1,468,804 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 |
| South Asian | 92.5% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 88.9% | 1 |
| Middle Eastern | 88.6% | 1 |
| Remaining individuals (not grpmax-eligible) | 87.9% | 1 |
| European (non-Finnish) | 87.4% | 1 |
| Amish (not grpmax-eligible) | 87.3% | 1 |
| Admixed American | 86.2% | 1 |
| Finnish (not grpmax-eligible) | 84.6% | 1 |
| African / African-American | 83.4% | 1 |

*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}

**ISCU** population constraint: LOEUF 1.542, pLI 0.002139, missense-Z -0.83688. *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):

- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.17, 70% of residues very-high.

**18 experimental structure(s)** (PDB): [5KZ5](https://www.rcsb.org/structure/5KZ5), [5WKP](https://www.rcsb.org/structure/5WKP), [5WLW](https://www.rcsb.org/structure/5WLW), [6NZU](https://www.rcsb.org/structure/6NZU), [6UXE](https://www.rcsb.org/structure/6UXE), [6W1D](https://www.rcsb.org/structure/6W1D).

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

*Describes the biological roles of ISCU (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:** ISCU's established molecular role includes ferrous iron binding. In Reactome, ISCU is annotated in disease pathway(s) including **Maturation of replicase proteins**.

**Disease mechanism (Reactome):** ISCU loss or alteration is curated in [Maturation of replicase proteins](https://reactome.org/content/detail/R-HSA-9694301).

### Pathways affected {#pathways}

ISCU participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Maturation of replicase proteins](https://reactome.org/content/detail/R-HSA-9694301) | curated |
| [Complex III assembly](https://reactome.org/content/detail/R-HSA-9865881) | other |
| [Maturation of TCA enzymes and regulation of TCA cycle](https://reactome.org/content/detail/R-HSA-9854311) | other |
| [Mitochondrial iron-sulfur cluster biogenesis](https://reactome.org/content/detail/R-HSA-1362409) | other |

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

**Molecular function:** ferrous iron binding, zinc ion binding, protein homodimerization activity, molecular adaptor activity, iron-sulfur cluster chaperone activity.

**Biological process:** intracellular iron ion homeostasis, iron-sulfur cluster assembly, [2Fe-2S] cluster assembly, [4Fe-4S] cluster assembly, positive regulation of mitochondrial electron transport, NADH to ubiquinone, negative regulation of iron ion import across plasma membrane.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-29.

**Submitter consensus:** conflicting (5 Benign, 1 Likely benign).

**Submission history:** 6 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-08-19 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-10-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[hereditary myopathy with lactic acidosis due to ISCU deficiency](https://sugi.bio/atlas/disease/hereditary-myopathy-with-lactic-acidosis-due-to-iscu-deficiency/).

**Reported phenotype names (ClinVar):** Hereditary myopathy with lactic acidosis due to ISCU deficiency, not provided, not specified, AllHighlyPenetrant, MYOPATHY WITH LACTIC ACIDOSIS, HEREDITARY, none provided.

## Similar variants {#similar}

Related ISCU variant pages (same residue, condition, or type): [ISCU p.Phe7Cys](/variant/iscu-p-phe7cys), [ISCU c.418+382G>C](/variant/iscu-c-418-plus-382g-c), [ISCU p.Ala105Gly](/variant/iscu-p-ala105gly), [ISCU c.419-162C>T](/variant/iscu-c-419-minus-162c-t), [ISCU p.Ala12Val](/variant/iscu-p-ala12val), [ISCU p.Gly50Glu](/variant/iscu-p-gly50glu), [ISCU c.418+702T>C](/variant/iscu-c-418-plus-702t-c), [ISCU p.Ala126Thr](/variant/iscu-p-ala126thr).

### 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 768575). 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.*