# NM_024306.5(FA2H):c.131C>A (p.Pro44Gln)

https://sugi.bio/variant/fa2h-p-pro44gln

## Summary

**FA2H p.Pro44Gln (c.131C>A)** is classified **Pathogenic/Likely pathogenic** in FA2H (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.8796); Ultra-rare (popmax 0.0142%, amr); Associated with Spastic paraplegia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs915291720 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0142%, amr)

## For patients & families {#patients}

This is a change in the FA2H gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to Spastic paraplegia.

*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 | [FA2H](https://sugi.bio/atlas/gene/FA2H/) |
| Protein change (HGVS p.) | p.Pro44Gln |
| Coding change (HGVS c.) | c.131C>A |
| MANE Select transcript | [NM_024306](https://www.ncbi.nlm.nih.gov/nuccore/NM_024306) |
| dbSNP | [rs915291720](https://www.ncbi.nlm.nih.gov/snp/rs915291720/) |
| Variant type | single nucleotide variant |
| Location | chr16:74774625-74774625 (GRCh38) |
| ClinVar | [VCV458305](https://www.ncbi.nlm.nih.gov/clinvar/variation/458305/) |

**All HGVS expressions:** `NC_000016.10:g.74774625G>T`, `NC_000016.9:g.74808523G>T`, `NG_017070.1:g.5207C>A`, `NM_024306.5:c.131C>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8796) — concordant with the pathogenic call
- REVEL 0.924 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.67 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.28, GERP 1.42, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 0.99** across the covering region of the MANE Select transcript (74,714,193–74,774,755), spanning 60,562 bp. Chi-square p 0.86. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for FA2H (462 scored positions, the nearest 17 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0142%** (amr) · FAF95 0.0066% · FAF99 0.00469% · 7/49,124 in the highest group · 9/1,516,080 alleles overall — ultra-rare (popmax 0.0142%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0142% | 7,018 |
| African / African-American | 0.00142% | 70,398 |
| European (non-Finnish) | 8.77e-05% | 1,140,352 |

*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}

**FA2H** population constraint: LOEUF 0.759, pLI 0.0053396, missense-Z -0.88456; 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.*

Curated gene–disease validity (ClinGen):

- **hereditary spastic paraplegia 35** — Definitive (AR)

## Protein context {#protein}

Residue **44** lies in the cytochrome b5 heme-binding domain.

AlphaFold model confidence (whole protein): pLDDT 85.53, 67% of residues very-high.

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

*Describes the biological roles of FA2H (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:** FA2H's established molecular role includes fatty acid 2-hydroxylase activity. p.Pro44Gln falls in the cytochrome b5 heme-binding domain.


### Pathways affected {#pathways}

FA2H participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sphingolipid de novo biosynthesis](https://reactome.org/content/detail/R-HSA-1660661) | curated |

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

**Molecular function:** fatty acid 2-hydroxylase activity, free fatty acid 2-hydroxylase activity, 4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase activity.

**Biological process:** ceramide biosynthetic process, establishment of skin barrier.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-13.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-13 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-07-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-15 |

## Associated conditions {#conditions}

[Spastic paraplegia](https://sugi.bio/atlas/disease/spastic-paraplegia/), [neurodegeneration with brain iron accumulation](https://sugi.bio/atlas/disease/neurodegeneration-with-brain-iron-accumulation/).

**Reported phenotype names (ClinVar):** Spastic paraplegia, Neurodegeneration with brain iron accumulation, not provided, none provided.

## Same-residue context {#hotspot}

Residue **44** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [FA2H p.Pro44fs](/variant/fa2h-p-pro44fs), [FA2H p.Pro44Ser](/variant/fa2h-p-pro44ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FA2H variant pages (same residue, condition, or type): [FA2H p.Pro44Ser](/variant/fa2h-p-pro44ser), [FA2H p.Pro44Thr](/variant/fa2h-p-pro44thr), [FA2H c.506+1G>C](/variant/fa2h-c-506-plus-1g-c), [FA2H p.Arg269His](/variant/fa2h-p-arg269his), [FA2H p.Met1Val](/variant/fa2h-p-met1val), [FA2H p.Pro148Leu](/variant/fa2h-p-pro148leu), [FA2H p.Pro44fs](/variant/fa2h-p-pro44fs), [FA2H p.Arg269Cys](/variant/fa2h-p-arg269cys).

### 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 458305). 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.*