Is HADHA p.Pro299Ser (c.895C>T) pathogenic?

HADHA p.Pro299Ser (c.895C>T) is classified Uncertain significance in HADHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-15). AlphaMissense: ambiguous (0.5302); Absent from gnomAD v4.1; Associated with long chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

What condition is associated with HADHA p.Pro299Ser (c.895C>T)?

HADHA p.Pro299Ser (c.895C>T) is associated with long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (ClinVar).

How common is HADHA p.Pro299Ser (c.895C>T) in the general population?

HADHA p.Pro299Ser (c.895C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HADHA p.Pro299Ser (c.895C>T)?

AlphaMissense predicts ambiguous (score 0.5302) — an in-silico prediction, not a clinical call.

HADHA p.Pro299Ser

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.895C>T · VCV4068987

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5302 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,559,964)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.5302	ambiguous
REVEL	0.786	moderately pathogenic-leaning
SaProt	LLR -10.76	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 53 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	29.1	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

No allele count reported in gnomAD v4.1 (AN 1,559,964). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HADHA
Protein: p.Pro299Ser
Coding: c.895C>T
MANE Select: NM_000182
Type: single nucleotide variant
Location: chr2:26214466 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 3 PDB

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)

Similar variants

HADHA p.Pro299His Uncertain significance ★★ ⚠ same residue
HADHA c.1689+2T>C Pathogenic/Likely pathogenic ★★ same condition
HADHA c.1690-2A>G Pathogenic/Likely pathogenic ★★ same condition
HADHA c.180+1G>A Pathogenic/Likely pathogenic ★★ same condition
HADHA c.180+3A>G Pathogenic/Likely pathogenic ★★ same condition
HADHA c.2000+1G>A Pathogenic/Likely pathogenic ★★ same condition
HADHA c.314+1G>C Likely pathogenic ★★ same condition
HADHA c.314+2T>G Likely pathogenic ★★ same condition

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-pro299ser (accessed [today's date]).

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