# NM_000414.4(HSD17B4):c.2176C>G (p.Leu726Val)

https://sugi.bio/variant/hsd17b4-p-leu726val

## Summary

**HSD17B4 p.Leu726Val (c.2176C>G)** is classified **Conflicting classifications of pathogenicity** in HSD17B4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-07). AlphaMissense: ambiguous (0.3812); Rare (popmax 0.1%, afr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs145728297 · 7 submitters · 4 linked conditions · AlphaMissense ambiguous · rare (popmax 0.1%, afr)

## For patients & families {#patients}

This is a change in the HSD17B4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, 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 | [HSD17B4](https://sugi.bio/atlas/gene/HSD17B4/) |
| Protein change (HGVS p.) | p.Leu726Val |
| Coding change (HGVS c.) | c.2176C>G |
| MANE Select transcript | [NM_000414](https://www.ncbi.nlm.nih.gov/nuccore/NM_000414) |
| dbSNP | [rs145728297](https://www.ncbi.nlm.nih.gov/snp/rs145728297/) |
| Variant type | single nucleotide variant |
| Location | chr5:119541959-119541959 (GRCh38) |
| ClinVar | [VCV287598](https://www.ncbi.nlm.nih.gov/clinvar/variation/287598/) |

**All HGVS expressions:** `NC_000005.10:g.119541959C>G`, `NC_000005.9:g.118877654C>G`, `NG_008182.1:g.94507C>G`, `NM_000414.4:c.2176C>G`, `NM_001199291.3:c.2251C>G`, `NM_001199292.2:c.2122C>G`, `NM_001292027.2:c.2104C>G`, `NM_001292028.2:c.1756C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3812) — no call either way
- REVEL 0.35 (indeterminate)
- SaProt LLR -8.126 (tolerated)
- Conservation: phyloP 7.581, GERP 1.87, phastCons 1 — highly conserved
- CADD: **PHRED 26.1**. 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 1.10** across the covering region of the MANE Select transcript (119,452,576–119,541,991), spanning 89,415 bp. Chi-square p 0.0022. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.1%** (afr) · FAF95 0.0818% · FAF99 0.0751% · 75/74,954 in the highest group · 82/1,613,054 alleles overall — rare (popmax 0.1%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.1% | 999 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,616 |
| Admixed American | 0.00167% | 59,916 |
| South Asian | 0.0011% | 91,054 |
| European (non-Finnish) | 8.48e-05% | 1,179,340 |

*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}

**HSD17B4** population constraint: LOEUF 0.854, pLI 0.0060678, missense-Z -0.65734. *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):

- **d-bifunctional protein deficiency** — Definitive (AR)
- **Perrault syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **726** lies in an α-helix; the scp2 domain.

AlphaFold model confidence (whole protein): pLDDT 89.65, 68% of residues very-high.

**7 experimental structure(s)** (PDB): [1IKT](https://www.rcsb.org/structure/1IKT), [1S9C](https://www.rcsb.org/structure/1S9C), [1ZBQ](https://www.rcsb.org/structure/1ZBQ), [6Z1W](https://www.rcsb.org/structure/6Z1W), [6Z1X](https://www.rcsb.org/structure/6Z1X), [8AF2](https://www.rcsb.org/structure/8AF2) — incl. mutant structure 6Z1W.

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

*Describes the biological roles of HSD17B4 (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:** HSD17B4's established molecular role includes enoyl-CoA hydratase activity. p.Leu726Val falls in the scp2 domain.


### Pathways affected {#pathways}

HSD17B4 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Beta-oxidation of pristanoyl-CoA](https://reactome.org/content/detail/R-HSA-389887) | curated |
| [Beta-oxidation of very long chain fatty acids](https://reactome.org/content/detail/R-HSA-390247) | curated |
| [Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol](https://reactome.org/content/detail/R-HSA-193368) | curated |
| [alpha-linolenic acid (ALA) metabolism](https://reactome.org/content/detail/R-HSA-2046106) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |
| [TYSND1 cleaves peroxisomal proteins](https://reactome.org/content/detail/R-HSA-9033500) | electronic |

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

**Molecular function:** enoyl-CoA hydratase activity, estradiol 17-beta-dehydrogenase [NAD(P)+] activity, 3-hydroxyacyl-CoA dehydratase activity, protein homodimerization activity, (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity.

**Biological process:** osteoblast differentiation, fatty acid beta-oxidation, androgen metabolic process, estrogen metabolic process, very long-chain fatty-acyl-CoA metabolic process, medium-chain fatty-acyl-CoA metabolic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-07.

**Submitter consensus:** conflicting (5 Uncertain significance, 2 Likely benign).

**Submission history:** 7 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-01-12 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-24 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-12-26 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-12-02 |
| New York Genome Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-14 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-10-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-07 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [Perrault syndrome 1](https://sugi.bio/atlas/disease/perrault-syndrome-1/), [d-bifunctional protein deficiency](https://sugi.bio/atlas/disease/d-bifunctional-protein-deficiency/), [Perrault syndrome](https://sugi.bio/atlas/disease/perrault-syndrome/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Bifunctional peroxisomal enzyme deficiency, Perrault syndrome 1, Perrault syndrome, HSD17B4-related disorder, HSD17B4-related condition, HSD17B4-related disorders, GONADAL DYSGENESIS, XX TYPE, WITH DEAFNESS, OVARIAN DYSGENESIS WITH SENSORINEURAL DEAFNESS.

## Similar variants {#similar}

Related HSD17B4 variant pages (same residue, condition, or type): [HSD17B4 c.1210-1G>A](/variant/hsd17b4-c-1210-minus-1g-a), [HSD17B4 c.1262-1G>A](/variant/hsd17b4-c-1262-minus-1g-a), [HSD17B4 c.1333+1G>C](/variant/hsd17b4-c-1333-plus-1g-c), [HSD17B4 c.1438-1G>A](/variant/hsd17b4-c-1438-minus-1g-a), [HSD17B4 c.1503+1G>A](/variant/hsd17b4-c-1503-plus-1g-a), [HSD17B4 c.1573+1G>A](/variant/hsd17b4-c-1573-plus-1g-a), [HSD17B4 c.1574-1G>A](/variant/hsd17b4-c-1574-minus-1g-a), [HSD17B4 c.1768-1G>A](/variant/hsd17b4-c-1768-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 287598). 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.*