Is HADHA p.Ala726Val (c.2177C>T) pathogenic?

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.

What condition is associated with HADHA p.Ala726Val (c.2177C>T)?

HADHA p.Ala726Val (c.2177C>T) is associated with long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (ClinVar).

How common is HADHA p.Ala726Val (c.2177C>T) in the general population?

HADHA p.Ala726Val (c.2177C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HADHA p.Ala726Val (c.2177C>T)?

AlphaMissense predicts likely benign (score 0.2332) — an in-silico prediction, not a clinical call.

HADHA p.Ala726Val

Q: How is Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2177C>T · VCV4069016

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2332 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.2332	likely benign
REVEL	0.626	indeterminate
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 53 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HADHA
Protein: p.Ala726Val
Coding: c.2177C>T
MANE Select: NM_001168241 · reported on NM_000182
Type: single nucleotide variant
Location: chr2:26191365 (GRCh38)

Full HADHA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

long chain 3-hydroxyacyl-CoA dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hadha-p-ala726val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown