# NM_000182.5(HADHA):c.2177C>T (p.Ala726Val)

https://sugi.bio/variant/hadha-p-ala726val

## Summary

**HADHA p.Ala726Val (c.2177C>T)** is classified **Uncertain significance** in HADHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-09). AlphaMissense: likely benign (0.2332); Absent from gnomAD v4.1; Associated with long chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the HADHA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to long chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

*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) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Photophobia — Very frequent (99-80%)
- Hypoglycemia — Very frequent (99-80%)
- Hypoketotic hypoglycemia — Very frequent (99-80%)
- Abnormal electroretinogram — Frequent (79-30%)
- Visual loss — Frequent (79-30%)
- Exotropia — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006867/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HADHA](https://sugi.bio/atlas/gene/HADHA/) |
| Protein change (HGVS p.) | p.Ala726Val |
| Coding change (HGVS c.) | c.2177C>T |
| MANE Select transcript | [NM_001168241](https://www.ncbi.nlm.nih.gov/nuccore/NM_001168241) (variant reported on NM_000182) |
| Variant type | single nucleotide variant |
| Location | chr2:26191365-26191365 (GRCh38) |
| ClinVar | [VCV4069016](https://www.ncbi.nlm.nih.gov/clinvar/variation/4069016/) |

**All HGVS expressions:** `LRG_747:g.58257C>T`, `LRG_747t1:c.2177C>T`, `NC_000002.11:g.26414234G>A`, `NC_000002.12:g.26191365G>A`, `NG_007121.2:g.58257C>T`, `NM_000182.5:c.2177C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2332)
- REVEL 0.626 (indeterminate)
- SaProt LLR -11.202 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 11.836, GERP 1.95, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.6**. 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 0.86** across the covering region of the MANE Select transcript (26,191,253–26,244,596), spanning 53,343 bp. Chi-square p 2.8e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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.*

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2025-01-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2025-01-09 |

## Associated conditions {#conditions}

[long chain 3-hydroxyacyl-CoA dehydrogenase deficiency](https://sugi.bio/atlas/disease/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/).

**Reported phenotype names (ClinVar):** Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, Deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase, LCHAD Deficiency.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 4069016). 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.*