# NM_024306.5(FA2H):c.707T>C (p.Phe236Ser)

https://sugi.bio/variant/fa2h-p-phe236ser

## Summary

**FA2H p.Phe236Ser (c.707T>C)** is classified **Pathogenic** in FA2H (ClinVar, No assertion criteria, 1 submitter; last evaluated 2012-04-01). AlphaMissense: likely pathogenic (0.6079); Very rare (popmax 0.000339%, nfe); Associated with hereditary spastic paraplegia 35.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs387907172 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the FA2H gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to hereditary spastic paraplegia 35.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Childhood |
| Diagnostic panels | FA2H is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Autosomal recessive spastic paraplegia type 35** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Spastic paraplegia — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Hyperreflexia — Very frequent (99-80%)
- Lower limb spasticity — Very frequent (99-80%)
- Babinski sign — Very frequent (99-80%)
- Foot dorsiflexor weakness — Very frequent (99-80%)
- Oculomotor apraxia — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010538/index) · [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.Phe236Ser |
| Coding change (HGVS c.) | c.707T>C |
| MANE Select transcript | [NM_024306](https://www.ncbi.nlm.nih.gov/nuccore/NM_024306) |
| dbSNP | [rs387907172](https://www.ncbi.nlm.nih.gov/snp/rs387907172/) |
| Variant type | single nucleotide variant |
| Location | chr16:74719067-74719067 (GRCh38) |
| ClinVar | [VCV31624](https://www.ncbi.nlm.nih.gov/clinvar/variation/31624/) |

**All HGVS expressions:** `NC_000016.10:g.74719067A>G`, `NC_000016.9:g.74752965A>G`, `NG_017070.1:g.60765T>C`, `NM_024306.5:c.707T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6079) — concordant with the pathogenic call
- REVEL 0.892 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.192 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 11.082, GERP 1.77, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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 4 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 **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,180,020 in the highest group · 4/1,613,990 alleles overall — very rare (popmax 0.000339%, nfe).

*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 **236** lies in the fatty acid hydroxylase 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.Phe236Ser falls in the fatty acid hydroxylase 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** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2012-04-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-04-01 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 35](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-35/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 35, SPASTIC PARAPLEGIA 35, AUTOSOMAL RECESSIVE, WITH OR WITHOUT NEURODEGENERATION, LEUKODYSTROPHY, DYSMYELINATING, AND SPASTIC PARAPARESIS WITH OR WITHOUT DYSTONIA, Spastic paraplegia 35, autosomal recessive, Spastic paraplegia 35.

## Same-residue context {#hotspot}

Residue **236** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FA2H p.Phe236fs](/variant/fa2h-p-phe236fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FA2H variant pages (same residue, condition, or type): [FA2H p.Phe236fs](/variant/fa2h-p-phe236fs), [FA2H c.363+2T>C](/variant/fa2h-c-363-plus-2t-c), [FA2H c.506+1G>C](/variant/fa2h-c-506-plus-1g-c), [FA2H c.786+1G>A](/variant/fa2h-c-786-plus-1g-a), [FA2H p.Arg127Ter](/variant/fa2h-p-arg127ter), [FA2H p.Arg189Ter](/variant/fa2h-p-arg189ter), [FA2H p.Arg197Ter](/variant/fa2h-p-arg197ter), [FA2H p.Arg235His](/variant/fa2h-p-arg235his).

### 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 31624). 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.*