# NM_004462.5(FDFT1):c.87C>G (p.Pro29=)

https://sugi.bio/variant/fdft1-p-pro29

## Summary

**FDFT1 p.Pro29= (c.87C>G)** is classified **Likely benign** in FDFT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-22). Very rare (popmax 0.00134%, afr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the FDFT1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [FDFT1](https://sugi.bio/atlas/gene/FDFT1/) |
| Protein change (HGVS p.) | p.Pro29= |
| Coding change (HGVS c.) | c.87C>G |
| MANE Select transcript | [NM_004462](https://www.ncbi.nlm.nih.gov/nuccore/NM_004462) |
| Variant type | single nucleotide variant |
| Location | chr8:11802919-11802919 (GRCh38) |
| ClinVar | [VCV4899537](https://www.ncbi.nlm.nih.gov/clinvar/variation/4899537/) |

**All HGVS expressions:** `NC_000008.10:g.11660428C>G`, `NC_000008.11:g.11802919C>G`, `NG_179350.1:g.20C>G`, `NM_001287742.2:c.87C>G`, `NM_001287743.2:c.87C>G`, `NM_001287744.2:c.-93-5875C>G`, `NM_001287745.2:c.-303C>G`, `NM_001287756.2:c.64+9C>G`, `NM_004462.5:c.87C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.971, GERP 0.597, phastCons 0.031 — weakly conserved position
- CADD: **PHRED 13.38**. 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 **0.26**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 9 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · FAF95 0.000183% · FAF99 0.00012% · 1/74,728 in the highest group · 9/1,608,462 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,117 |
| African / African-American (grpmax) | 0.00134% | 74,728 |
| European (non-Finnish) | 0.00051% | 196,254 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**FDFT1** population constraint: LOEUF 1.764, pLI 1.4695e-26, missense-Z -5.832. *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 89.14, 74% of residues very-high.

**32 experimental structure(s)** (PDB): [1EZF](https://www.rcsb.org/structure/1EZF), [3ASX](https://www.rcsb.org/structure/3ASX), [3LEE](https://www.rcsb.org/structure/3LEE), [3Q2Z](https://www.rcsb.org/structure/3Q2Z), [3Q30](https://www.rcsb.org/structure/3Q30), [3V66](https://www.rcsb.org/structure/3V66) — incl. mutant structure 3WEI.

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

*Describes the biological roles of FDFT1 (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.*


### Pathways affected {#pathways}

FDFT1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of gene expression by SREBF (SREBP)](https://reactome.org/content/detail/R-HSA-2426168) | curated |
| [Lanosterol biosynthesis](https://reactome.org/content/detail/R-HSA-9969896) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-01-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-01-22 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related FDFT1 variant pages (same residue, condition, or type): [FDFT1 c.100-85G>C](/variant/fdft1-c-100-minus-85g-c), [FDFT1 p.Ala333Ser](/variant/fdft1-p-ala333ser), [FDFT1 p.Asn265Ser](/variant/fdft1-p-asn265ser), [FDFT1 p.Gly151Asp](/variant/fdft1-p-gly151asp), [FDFT1 p.Ile252Thr](/variant/fdft1-p-ile252thr), [FDFT1 p.Phe210Leu](/variant/fdft1-p-phe210leu), [FDFT1 p.Ser102Cys](/variant/fdft1-p-ser102cys), [FDFT1 c.100-179C>G](/variant/fdft1-c-100-minus-179c-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4899537). 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.*