# NM_024867.4(SPEF2):c.796T>C (p.Ser266Pro)

https://sugi.bio/variant/spef2-p-ser266pro

## Summary

**SPEF2 p.Ser266Pro (c.796T>C)** is classified **Uncertain significance** in SPEF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-10). AlphaMissense: likely benign (0.0912); Ultra-rare (popmax 0.034%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs767797491 · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.034%, mid)

## For patients & families {#patients}

This is a change in the SPEF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [SPEF2](https://sugi.bio/atlas/gene/SPEF2/) |
| Protein change (HGVS p.) | p.Ser266Pro |
| Coding change (HGVS c.) | c.796T>C |
| MANE Select transcript | [NM_024867](https://www.ncbi.nlm.nih.gov/nuccore/NM_024867) |
| dbSNP | [rs767797491](https://www.ncbi.nlm.nih.gov/snp/rs767797491/) |
| Variant type | single nucleotide variant |
| Location | chr5:35654544-35654544 (GRCh38) |
| ClinVar | [VCV2271477](https://www.ncbi.nlm.nih.gov/clinvar/variation/2271477/) |

**All HGVS expressions:** `NC_000005.10:g.35654544T>C`, `NC_000005.9:g.35654646T>C`, `NM_024867.4:c.796T>C`, `NM_144722.4:c.796T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0912)
- REVEL 0.022 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.296 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.44, GERP -1.12, phastCons 0.964 — weakly conserved position
- CADD: **PHRED 17.65**. 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 1.02** across the covering region of the MANE Select transcript (35,617,998–35,814,550), spanning 196,552 bp. Chi-square p 0.46. 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 (T>G, Δ0.63 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 **0.034%** (mid) · FAF95 0.00598% · FAF99 0.00248% · 2/5,884 in the highest group · 6/1,577,042 alleles overall — ultra-rare (popmax 0.034%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.034% | 2,942 |
| Remaining individuals (not grpmax-eligible) | 0.00165% | 60,708 |
| European (non-Finnish) | 0.000257% | 389,539 |

*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}

**SPEF2** population constraint: LOEUF 0.923, pLI 1.2592e-40, missense-Z 0.49092. *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):

- **primary ciliary dyskinesia** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.30, 16% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-10.

**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 | 2022-01-10 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related SPEF2 variant pages (same residue, condition, or type): [SPEF2 p.Asp797Gly](/variant/spef2-p-asp797gly), [SPEF2 p.Glu116Lys](/variant/spef2-p-glu116lys), [SPEF2 p.Glu1752Gln](/variant/spef2-p-glu1752gln), [SPEF2 p.Ala1122Thr](/variant/spef2-p-ala1122thr), [SPEF2 p.Ala1323Val](/variant/spef2-p-ala1323val), [SPEF2 p.Ala1355Thr](/variant/spef2-p-ala1355thr), [SPEF2 p.Ala1405Ser](/variant/spef2-p-ala1405ser), [SPEF2 p.Ala1772Thr](/variant/spef2-p-ala1772thr).

### 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 2271477). 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.*