# NM_001040167.2(LFNG):c.723C>T (p.Ser241=)

https://sugi.bio/variant/lfng-p-ser241

## Summary

**LFNG p.Ser241= (c.723C>T)** is classified **Likely benign** in LFNG (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.0919%, afr); Associated with spondylocostal dysostosis 3, autosomal recessive.

**At a glance:** Likely benign · review: Single submitter · rsID rs115678269 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0919%, afr)

## For patients & families {#patients}

This is a change in the LFNG gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to spondylocostal dysostosis 3, autosomal recessive.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004973/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LFNG](https://sugi.bio/atlas/gene/LFNG/) |
| Protein change (HGVS p.) | p.Ser241= |
| Coding change (HGVS c.) | c.723C>T |
| MANE Select transcript | [NM_001040167](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040167) |
| dbSNP | [rs115678269](https://www.ncbi.nlm.nih.gov/snp/rs115678269/) |
| Variant type | single nucleotide variant |
| Location | chr7:2525555-2525555 (GRCh38) |
| ClinVar | [VCV534226](https://www.ncbi.nlm.nih.gov/clinvar/variation/534226/) |

**All HGVS expressions:** `NC_000007.13:g.2565189C>T`, `NC_000007.14:g.2525555C>T`, `NG_008109.2:g.18027C>T`, `NM_001040167.2:c.723C>T`, `NM_001040168.2:c.723C>T`, `NM_001166355.2:c.510C>T`, `NM_002304.3:c.336C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.63) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.318, GERP -3.15 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 20.4**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.12**, acceptor gain **0.00**, donor gain **0.63**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.63**.
- Pangolin: Δ**0.37** (gain), gain 0.37 / loss 0.03. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0919%** (afr) · FAF95 0.0744% · FAF99 0.0681% · 69/75,064 in the highest group · 117/1,612,246 alleles overall — ultra-rare (popmax 0.0919%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0919% | 1,088 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,919 |
| South Asian | 0.0033% | 30,336 |
| European (non-Finnish) | 0.00305% | 32,771 |
| East Asian | 0.00223% | 44,866 |
| Admixed American | 0.00167% | 59,952 |

*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}

**LFNG** population constraint: LOEUF 0.755, pLI 0.02119, missense-Z -0.14725; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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}


AlphaFold model confidence (whole protein): pLDDT 83.66, 67% of residues very-high.

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

*Describes the biological roles of LFNG (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:** LFNG's established molecular role includes O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity. In Reactome, LFNG is annotated in disease pathway(s) including **Defective LFNG causes SCDO3**.

**Disease mechanism (Reactome):** LFNG loss or alteration is curated in [Defective LFNG causes SCDO3](https://reactome.org/content/detail/R-HSA-5083630).

### Pathways affected {#pathways}

LFNG participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective LFNG causes SCDO3](https://reactome.org/content/detail/R-HSA-5083630) | curated |
| [Nephron development](https://reactome.org/content/detail/R-HSA-9831926) | electronic |
| [Pre-NOTCH Processing in Golgi](https://reactome.org/content/detail/R-HSA-1912420) | electronic |
| [Somitogenesis](https://reactome.org/content/detail/R-HSA-9824272) | electronic |

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

**Molecular function:** O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity.

**Biological process:** regulation of somitogenesis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-22.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-04-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-22 |

## Associated conditions {#conditions}

[spondylocostal dysostosis 3, autosomal recessive](https://sugi.bio/atlas/disease/spondylocostal-dysostosis-3-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Spondylocostal dysostosis 3, autosomal recessive, LFNG-related disorder, LFNG-Related Spondylocostal Dysostosis, Autosomal Recessive, LFNG-related condition.

## Similar variants {#similar}

Related LFNG variant pages (same residue, condition, or type): [LFNG p.Thr145Met](/variant/lfng-p-thr145met), [LFNG c.482-3C>T](/variant/lfng-c-482-minus-3c-t), [LFNG p.Ala95Val](/variant/lfng-p-ala95val), [LFNG p.Ala99Thr](/variant/lfng-p-ala99thr), [LFNG p.Arg187Cys](/variant/lfng-p-arg187cys), [LFNG p.Arg239Trp](/variant/lfng-p-arg239trp), [LFNG p.Arg246His](/variant/lfng-p-arg246his), [LFNG p.Arg341Gln](/variant/lfng-p-arg341gln).

### 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 534226). 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.*