# NM_001040167.2(LFNG):c.623G>C (p.Arg208Pro)

https://sugi.bio/variant/lfng-p-arg208pro

## Summary

**LFNG p.Arg208Pro (c.623G>C)** is classified **Uncertain significance** in LFNG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely benign (0.0674); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the LFNG 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 | [LFNG](https://sugi.bio/atlas/gene/LFNG/) |
| Protein change (HGVS p.) | p.Arg208Pro |
| Coding change (HGVS c.) | c.623G>C |
| MANE Select transcript | [NM_001040167](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040167) |
| Variant type | single nucleotide variant |
| Location | chr7:2525455-2525455 (GRCh38) |
| ClinVar | [VCV4046931](https://www.ncbi.nlm.nih.gov/clinvar/variation/4046931/) |

**All HGVS expressions:** `NC_000007.13:g.2565089G>C`, `NC_000007.14:g.2525455G>C`, `NG_008109.2:g.17927G>C`, `NM_001040167.2:c.623G>C`, `NM_001040168.2:c.623G>C`, `NM_001166355.2:c.410G>C`, `NM_002304.3:c.236G>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** (0.0674)
- REVEL 0.176 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.615 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.954, GERP -2.19, phastCons 0.012 — weakly conserved position
- CADD: **PHRED 20.1**. 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 1.01** across the covering region of the MANE Select transcript (2,519,862–2,525,690), spanning 5,828 bp. Chi-square p 0.78. 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 (G>A, Δ0.79 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 **0.0164%** (mid) · FAF95 0.000359% · FAF99 0.00026% · 1/6,084 in the highest group · 11/1,612,640 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| African / African-American | 0.00133% | 74,948 |
| European (non-Finnish) | 0.000763% | 131,099 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-27.

**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 | 2025-03-27 |

## 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 LFNG variant pages (same residue, condition, or type): [LFNG p.Arg208Gly](/variant/lfng-p-arg208gly), [LFNG p.Arg208Leu](/variant/lfng-p-arg208leu), [LFNG p.Ala99Thr](/variant/lfng-p-ala99thr), [LFNG p.Arg187Cys](/variant/lfng-p-arg187cys), [LFNG p.Arg341Gln](/variant/lfng-p-arg341gln), [LFNG p.Arg4Cys](/variant/lfng-p-arg4cys), [LFNG p.Asp231Asn](/variant/lfng-p-asp231asn), [LFNG p.Glu190Val](/variant/lfng-p-glu190val).

### 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 4046931). 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.*