# NM_001244008.2(KIF1A):c.2976A>G (p.Ser992=)

https://sugi.bio/variant/kif1a-p-ser992

## Summary

**KIF1A p.Ser992= (c.2976A>G)** is classified **Uncertain significance** in KIF1A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-08). Very rare (popmax 0.00051%, nfe); Associated with hereditary spastic paraplegia 30.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2049077964 · 4 submitters · 3 linked conditions · very rare (popmax 0.00051%, nfe)

## For patients & families {#patients}

This is a change in the KIF1A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, and is linked to hereditary spastic paraplegia 30.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult |
| Diagnostic panels | KIF1A is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Autosomal spastic paraplegia type 30** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Lower limb spasticity — Very frequent (99-80%)
- Spastic gait — Very frequent (99-80%)
- Unsteady gait — Very frequent (99-80%)
- Lower limb hyperreflexia — Very frequent (99-80%)
- Babinski sign — Very frequent (99-80%)
- Progressive spastic paraplegia — Very frequent (99-80%)
- Leg muscle stiffness — Very frequent (99-80%)
- Abnormal saccadic eye movements — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016942/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [KIF1A](https://sugi.bio/atlas/gene/KIF1A/) |
| Protein change (HGVS p.) | p.Ser992= |
| Coding change (HGVS c.) | c.2976A>G |
| MANE Select transcript | [NM_001244008](https://www.ncbi.nlm.nih.gov/nuccore/NM_001244008) |
| dbSNP | [rs2049077964](https://www.ncbi.nlm.nih.gov/snp/rs2049077964/) |
| Variant type | single nucleotide variant |
| Location | chr2:240750430-240750430 (GRCh38) |
| ClinVar | [VCV852799](https://www.ncbi.nlm.nih.gov/clinvar/variation/852799/) |

**All HGVS expressions:** `LRG_367:g.74778A>G`, `NC_000002.11:g.241689847T>C`, `NC_000002.12:g.240750430T>C`, `NG_029724.1:g.74778A>G`, `NM_001244008.2:c.2976A>G`, `NM_001320705.2:c.2700A>G`, `NM_001330289.2:c.2700A>G`, `NM_001330290.2:c.2775A>G`, `NM_001379631.1:c.3051A>G`, `NM_001379632.1:c.2925A>G`, `NM_001379633.1:c.2949A>G`, `NM_001379634.1:c.2775A>G`, `NM_001379635.1:c.2775A>G`, `NM_001379636.1:c.2673A>G`, `NM_001379637.1:c.2748A>G`, `NM_001379638.1:c.2700A>G`, `NM_001379639.1:c.2673A>G`, `NM_001379640.1:c.2673A>G`, `NM_001379641.1:c.2673A>G`, `NM_001379642.1:c.2949A>G`, `NM_001379645.1:c.2949A>G`, `NM_001379646.1:c.2775A>G`, `NM_001379648.1:c.2748A>G`, `NM_001379649.1:c.2673A>G`, `NM_001379650.1:c.2673A>G`, `NM_001379651.1:c.2673A>G`, `NM_001379653.1:c.2673A>G`, `NM_004321.8:c.2673A>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 6.11, GERP 1.26, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.66**. 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 **0.00051%** (nfe) · FAF95 0.000183% · FAF99 0.000121% · 6/1,176,764 in the highest group · 6/1,610,178 alleles overall — very rare (popmax 0.00051%, nfe).

*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}

**KIF1A** population constraint: LOEUF 0.304, pLI 1, missense-Z 5.035; ClinGen dosage — haploinsufficiency 0/3, 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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **992** lies in a UniProt-annotated variant site (in spg30a).

AlphaFold model confidence (whole protein): pLDDT 71.38, 20% of residues very-high.

**21 experimental structure(s)** (PDB): [4EGX](https://www.rcsb.org/structure/4EGX), [4EJQ](https://www.rcsb.org/structure/4EJQ), [4UXO](https://www.rcsb.org/structure/4UXO), [4UXP](https://www.rcsb.org/structure/4UXP), [4UXR](https://www.rcsb.org/structure/4UXR), [4UXS](https://www.rcsb.org/structure/4UXS) — incl. mutant structure 8UTT.

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

*Describes the biological roles of KIF1A (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:** KIF1A's established molecular role includes identical protein binding.


### Pathways affected {#pathways}

KIF1A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-dependent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811434) | curated |
| [Kinesins](https://reactome.org/content/detail/R-HSA-983189) | curated |

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

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-08.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-19 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-08 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-29 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 30](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-30/), [neuropathy, hereditary sensory, type 2C](https://sugi.bio/atlas/disease/neuropathy-hereditary-sensory-type-2c/), [intellectual disability, autosomal dominant 9](https://sugi.bio/atlas/disease/intellectual-disability-autosomal-dominant-9/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 30, Intellectual disability, autosomal dominant 9, Neuropathy, hereditary sensory, type 2C, not provided, not specified, none provided, KIF1A-Related HSAN2 (HSAN2C), Hereditary sensory and autonomic neuropathy type IIC, KIF1A-Related Neurodevelopmental Disorder, NESCAV SYNDROME.

## Similar variants {#similar}

Related KIF1A variant pages (same residue, condition, or type): [KIF1A c.2582+1G>A](/variant/kif1a-c-2582-plus-1g-a), [KIF1A c.798+1G>A](/variant/kif1a-c-798-plus-1g-a), [KIF1A p.Ala255Asp](/variant/kif1a-p-ala255asp), [KIF1A p.Ala85Asp](/variant/kif1a-p-ala85asp), [KIF1A p.Arg11Gln](/variant/kif1a-p-arg11gln), [KIF1A p.Arg11Trp](/variant/kif1a-p-arg11trp), [KIF1A p.Arg13Cys](/variant/kif1a-p-arg13cys), [KIF1A p.Arg13His](/variant/kif1a-p-arg13his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 852799). 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.*