Is HADHB p.Pro7= (c.21C>G) pathogenic?

HADHB p.Pro7= (c.21C>G) is classified Likely benign in HADHB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). Very rare (popmax 0.00137%, afr); Associated with mitochondrial trifunctional protein deficiency.

What condition is associated with HADHB p.Pro7= (c.21C>G)?

HADHB p.Pro7= (c.21C>G) is associated with mitochondrial trifunctional protein deficiency (ClinVar).

How common is HADHB p.Pro7= (c.21C>G) in the general population?

HADHB p.Pro7= (c.21C>G) is very rare (popmax 0.00137%, afr) (gnomAD).

HADHB p.Pro7=

Q: How is Mitochondrial trifunctional protein deficiency inherited?

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

c.21C>G · rs2465647208 · VCV1939889

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Conditions

mitochondrial trifunctional protein deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.23	GERP -3.4, phastCons 0.008
Overall
CADD	1.303	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00137% African / African-American · 1/73,046 alleles

Overall 6.65e-05% 1/1,504,652 alleles · very rare exomes 1/1,352,368 · genomes 0/152,284 · joint denominator

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.Pro7=
Coding: c.21C>G
MANE Select: NM_000183
dbSNP: rs2465647208
Type: single nucleotide variant
Location: chr2:26254275 (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-pro7 (accessed [today's date]).

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