Is HADHB p.Pro429= (c.1287A>G) pathogenic?

HADHB p.Pro429= (c.1287A>G) is classified Likely benign in HADHB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-20). Very rare (popmax 0.0022%, sas); Associated with mitochondrial trifunctional protein deficiency.

What condition is associated with HADHB p.Pro429= (c.1287A>G)?

HADHB p.Pro429= (c.1287A>G) is associated with mitochondrial trifunctional protein deficiency (ClinVar).

How common is HADHB p.Pro429= (c.1287A>G) in the general population?

HADHB p.Pro429= (c.1287A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

HADHB p.Pro429=

Q: How is Mitochondrial trifunctional protein deficiency inherited?

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

c.1287A>G · rs1240736535 · VCV2147516

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

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 -6	GERP -3.6
Overall
CADD	0.917	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,068 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,613,466 alleles · very rare exomes 3/1,461,504 · genomes 1/151,962 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,534
Admixed American	0.00167%	59,974
African / African-American	0.00134%	74,818

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.Pro429=
Coding: c.1287A>G
MANE Select: NM_000183
dbSNP: rs1240736535
Type: single nucleotide variant
Location: chr2:26285469 (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-pro429 (accessed [today's date]).

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