# NM_001371986.1(UNC80):c.1818G>A (p.Pro606=)

https://sugi.bio/variant/unc80-p-pro606

## Summary

**UNC80 p.Pro606= (c.1818G>A)** is classified **Conflicting classifications of pathogenicity** in UNC80 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-28). Rare (popmax 0.406%, afr); Associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs61742726 · 6 submitters · 1 linked condition · rare (popmax 0.406%, afr)

## For patients & families {#patients}

This is a change in the UNC80 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to hypotonia, infantile, with psychomotor retardation and characteristic facies 2.

*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) | Infancy, Neonatal |
| Diagnostic panels | UNC80 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Hypotonia-speech impairment-severe cognitive delay syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Strabismus — Very frequent (99-80%)
- Esotropia — Very frequent (99-80%)
- Delayed speech and language development — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Motor delay — Very frequent (99-80%)
- Absent speech — Very frequent (99-80%)
- Floppy infant — Very frequent (99-80%)
- Tapered distal phalanges of finger — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018458/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [UNC80](https://sugi.bio/atlas/gene/UNC80/) |
| Protein change (HGVS p.) | p.Pro606= |
| Coding change (HGVS c.) | c.1818G>A |
| MANE Select transcript | [NM_001371986](https://www.ncbi.nlm.nih.gov/nuccore/NM_001371986) |
| dbSNP | [rs61742726](https://www.ncbi.nlm.nih.gov/snp/rs61742726/) |
| Variant type | single nucleotide variant |
| Location | chr2:209819117-209819117 (GRCh38) |
| ClinVar | [VCV738185](https://www.ncbi.nlm.nih.gov/clinvar/variation/738185/) |

**All HGVS expressions:** `NC_000002.11:g.210683841G>A`, `NC_000002.12:g.209819117G>A`, `NG_051361.1:g.52193G>A`, `NM_001371986.1:c.1818G>A`, `NM_032504.2:c.1818G>A`, `NM_182587.4:c.1818G>A`

## 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 -1.092, GERP -3.75 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.653**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.406%** (afr) · FAF95 0.368% · FAF99 0.353% · 297/73,128 in the highest group · 435/1,552,138 alleles overall — rare (popmax 0.406%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.406% | 246 |
| Remaining individuals (not grpmax-eligible) | 0.0548% | 1,826 |
| Middle Eastern | 0.0334% | 2,998 |
| Admixed American | 0.0255% | 3,923 |
| European (non-Finnish) | 0.0075% | 13,338 |
| East Asian | 0.00489% | 20,458 |
| South Asian | 0.00238% | 42,023 |

*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}

**UNC80** population constraint: LOEUF 0.48, pLI 0.0041479, missense-Z 5.0069; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **hypotonia, infantile, with psychomotor retardation and characteristic facies 2** — Definitive (AR)

## Protein context {#protein}


**3 experimental structure(s)** (PDB): [7SX3](https://www.rcsb.org/structure/7SX3), [7SX4](https://www.rcsb.org/structure/7SX4), [7WJI](https://www.rcsb.org/structure/7WJI).

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

*Describes the biological roles of UNC80 (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.*


### Pathways affected {#pathways}

UNC80 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

**Biological process:** sodium ion transmembrane transport, regulation of neuronal action potential.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (3 Likely benign, 2 Benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CENTOGENE GmbH and LLC - Guiding Precision Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-22 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2024-11-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-05 |

## Associated conditions {#conditions}

[hypotonia, infantile, with psychomotor retardation and characteristic facies 2](https://sugi.bio/atlas/disease/hypotonia-infantile-with-psychomotor-retardation-and-characteristic-facies-2/).

**Reported phenotype names (ClinVar):** Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, not provided, not specified, none provided, UNC80 Deficiency, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **606** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [UNC80 p.Pro606fs](/variant/unc80-p-pro606fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related UNC80 variant pages (same residue, condition, or type): [UNC80 p.Pro606Leu](/variant/unc80-p-pro606leu), [UNC80 p.Pro606Ser](/variant/unc80-p-pro606ser), [UNC80 c.4110+1G>C](/variant/unc80-c-4110-plus-1g-c), [UNC80 c.8772+1G>A](/variant/unc80-c-8772-plus-1g-a), [UNC80 p.Arg1076Ter](/variant/unc80-p-arg1076ter), [UNC80 p.Arg1110Ter](/variant/unc80-p-arg1110ter), [UNC80 p.Arg1285Ter](/variant/unc80-p-arg1285ter), [UNC80 p.Arg1355Ter](/variant/unc80-p-arg1355ter).

### 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 738185). 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.*