# NM_198525.3(KIF7):c.993C>G (p.Ser331=)

https://sugi.bio/variant/kif7-p-ser331

## Summary

**KIF7 p.Ser331= (c.993C>G)** is classified **Likely benign** in KIF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-14). Very rare (popmax 0.00274%, afr); Associated with acrocallosal syndrome.

**At a glance:** Likely benign · review: Single submitter · rsID rs1365475877 · 1 submitter · 1 linked condition · very rare (popmax 0.00274%, afr)

## For patients & families {#patients}

This is a change in the KIF7 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to acrocallosal syndrome.

*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 | 25 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005721/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [KIF7](https://sugi.bio/atlas/gene/KIF7/) |
| Protein change (HGVS p.) | p.Ser331= |
| Coding change (HGVS c.) | c.993C>G |
| MANE Select transcript | [NM_198525](https://www.ncbi.nlm.nih.gov/nuccore/NM_198525) |
| dbSNP | [rs1365475877](https://www.ncbi.nlm.nih.gov/snp/rs1365475877/) |
| Variant type | single nucleotide variant |
| Location | chr15:89648705-89648705 (GRCh38) |
| ClinVar | [VCV1594065](https://www.ncbi.nlm.nih.gov/clinvar/variation/1594065/) |

**All HGVS expressions:** `NC_000015.10:g.89648705G>C`, `NC_000015.9:g.90191936G>C`, `NG_030338.1:g.11747C>G`, `NM_198525.3:c.993C>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 -2.022, GERP -5.34 — fast-evolving / accelerated position
- CADD: **PHRED 4.752**. 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 (G>T, Δ0.26 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 **0.00274%** (afr) · FAF95 0.000455% · FAF99 0.00017% · 2/73,026 in the highest group · 2/1,536,152 alleles overall — very rare (popmax 0.00274%, afr).

*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}

**KIF7** population constraint: LOEUF 1.038, pLI 3.0938e-31, missense-Z -2.3744; 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.*

## Protein context {#protein}

Residue **331** lies in the kinesin motor domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 68.07, 18% of residues very-high.

**5 experimental structure(s)** (PDB): [2XT3](https://www.rcsb.org/structure/2XT3), [4A14](https://www.rcsb.org/structure/4A14), [6MLQ](https://www.rcsb.org/structure/6MLQ), [6MLR](https://www.rcsb.org/structure/6MLR), [7RX0](https://www.rcsb.org/structure/7RX0).

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

*Describes the biological roles of KIF7 (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:** KIF7's established molecular role includes microtubule motor activity. p.Ser331= falls in the kinesin motor domain.


### Pathways affected {#pathways}

KIF7 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Hedgehog 'off' state](https://reactome.org/content/detail/R-HSA-5610787) | curated |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |

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

**Molecular function:** microtubule motor activity.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-14.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-14 |

## Associated conditions {#conditions}

[acrocallosal syndrome](https://sugi.bio/atlas/disease/acrocallosal-syndrome/).

**Reported phenotype names (ClinVar):** Acrocallosal syndrome, HALLUX DUPLICATION, POSTAXIAL POLYDACTYLY, AND ABSENCE OF CORPUS CALLOSUM, Schinzel syndrome 1, Absence of corpus callosum with unusual facial appearance, mental deficiency, duplication of the halluces and polydactyly.

## Similar variants {#similar}

Related KIF7 variant pages (same residue, condition, or type): [KIF7 c.1443+2T>C](/variant/kif7-c-1443-plus-2t-c), [KIF7 c.1561-1G>A](/variant/kif7-c-1561-minus-1g-a), [KIF7 c.1789-2A>G](/variant/kif7-c-1789-minus-2a-g), [KIF7 c.2593-3C>G](/variant/kif7-c-2593-minus-3c-g), [KIF7 c.328+2T>G](/variant/kif7-c-328-plus-2t-g), [KIF7 c.3518-1G>C](/variant/kif7-c-3518-minus-1g-c), [KIF7 c.923+2T>G](/variant/kif7-c-923-plus-2t-g), [KIF7 p.Arg1111Ter](/variant/kif7-p-arg1111ter).

### 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 1594065). 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.*