# NM_001366661.1(CLUH):c.1060C>T (p.Pro354Ser)

https://sugi.bio/variant/cluh-p-pro354ser

## Summary

**CLUH p.Pro354Ser (c.1060C>T)** is classified **Uncertain significance** in CLUH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely pathogenic (0.5655); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1372079320 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CLUH 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 | [CLUH](https://sugi.bio/atlas/gene/CLUH/) |
| Protein change (HGVS p.) | p.Pro354Ser |
| Coding change (HGVS c.) | c.1060C>T |
| MANE Select transcript | [NM_001366661](https://www.ncbi.nlm.nih.gov/nuccore/NM_001366661) |
| dbSNP | [rs1372079320](https://www.ncbi.nlm.nih.gov/snp/rs1372079320/) |
| Variant type | single nucleotide variant |
| Location | chr17:2700791-2700791 (GRCh38) |
| ClinVar | [VCV2340068](https://www.ncbi.nlm.nih.gov/clinvar/variation/2340068/) |

**All HGVS expressions:** `NC_000017.10:g.2604085G>A`, `NC_000017.11:g.2700791G>A`, `NG_135168.1:g.678G>A`, `NM_001366661.1:c.1060C>T`, `NM_001366662.1:c.946C>T`, `NM_015229.4:c.1060C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5655)
- REVEL 0.593 (indeterminate)
- SaProt LLR -8.192 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 9.998, GERP 2.33, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P316S** vs ClinVar **P354S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 26.1**. 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 0.76** across the covering region of the MANE Select transcript (2,700,779–2,703,470), spanning 2,691 bp. Chi-square p 6.9e-06. 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 (G>C, Δ0.33 acceptor 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: **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}

**CLUH** population constraint: LOEUF 0.799, pLI 2.3969e-16, missense-Z -0.94971. *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 **354** lies in the clu domain.

AlphaFold model confidence (whole protein): pLDDT 83.11, 59% of residues very-high.

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

*Describes the biological roles of CLUH (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:** CLUH's established molecular role includes mRNA binding. p.Pro354Ser falls in the clu domain.


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

**Molecular function:** mRNA binding.

**Biological process:** mitochondrion organization, intracellular distribution of mitochondria.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-28.

**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 | 2022-12-28 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CLUH variant pages (same residue, condition, or type): [CLUH p.Ala671Val](/variant/cluh-p-ala671val), [CLUH p.Ala700=](/variant/cluh-p-ala700), [CLUH p.Glu1228=](/variant/cluh-p-glu1228), [CLUH p.Thr201=](/variant/cluh-p-thr201), [CLUH c.1025+1G>A](/variant/cluh-c-1025-plus-1g-a), [CLUH p.Ala1076Thr](/variant/cluh-p-ala1076thr), [CLUH p.Ala1257Ser](/variant/cluh-p-ala1257ser), [CLUH p.Ala1320Gly](/variant/cluh-p-ala1320gly).

### 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 2340068). 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.*