Is HADHB p.Pro299= (c.897C>G) pathogenic?

HADHB p.Pro299= (c.897C>G) is classified Likely benign in HADHB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-15). Very rare (popmax 0.00127%, nfe); Associated with mitochondrial trifunctional protein deficiency.

What condition is associated with HADHB p.Pro299= (c.897C>G)?

HADHB p.Pro299= (c.897C>G) is associated with mitochondrial trifunctional protein deficiency (ClinVar).

How common is HADHB p.Pro299= (c.897C>G) in the general population?

HADHB p.Pro299= (c.897C>G) is very rare (popmax 0.00127%, nfe) (gnomAD).

HADHB p.Pro299=

Q: How is Mitochondrial trifunctional protein deficiency inherited?

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

c.897C>G · rs768056398 · VCV1950734

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Conditions

mitochondrial trifunctional protein deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.006	GERP 1.1, phastCons 0.75
Overall
CADD	9.321	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,178,710 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.00103% 15/1,460,206 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HADHB
Protein: p.Pro299=
Coding: c.897C>G
MANE Select: NM_000183
dbSNP: rs768056398
Type: single nucleotide variant
Location: chr2:26280079 (GRCh38)
Gene constraint: LOEUF 1.145 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.89 · 3 PDB

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

Disease context

mitochondrial trifunctional protein deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial trifunctional protein deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

HADHB c.1149+2T>C Likely pathogenic ★★ same condition
HADHB c.1150-1G>T Likely pathogenic ★★ same condition
HADHB c.1389+5G>A Pathogenic/Likely pathogenic ★★ same condition
HADHB c.209+1G>C Pathogenic ★★ same condition
HADHB c.210-1G>T Pathogenic/Likely pathogenic ★★ same condition
HADHB c.254+1G>A Pathogenic/Likely pathogenic ★★ same condition
HADHB c.255-2A>G Pathogenic/Likely pathogenic ★★ same condition
HADHB c.354+2T>C 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/hadhb-p-pro299 (accessed [today's date]).

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