Is FH p.Val139= (c.417G>A) pathogenic?

FH p.Val139= (c.417G>A) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-25). Very rare (popmax 0.00017%, nfe); Associated with fumaric aciduria.

What condition is associated with FH p.Val139= (c.417G>A)?

FH p.Val139= (c.417G>A) is associated with fumaric aciduria, hereditary neoplastic syndrome (ClinVar).

How common is FH p.Val139= (c.417G>A) in the general population?

FH p.Val139= (c.417G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Fumaric aciduria inherited?

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

FH p.Val139=

c.417G>A · rs768341401 · VCV573543

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

fumaric aciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.87	acceptor gain · deltas
Pangolin	Δ0.43	gain · loss 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.7	GERP 1.7, phastCons 1
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,848 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,788 alleles · very rare exomes 2/1,461,612 · genomes 0/152,176 · 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: FH
Protein: p.Val139=
Coding: c.417G>A
MANE Select: NM_000143
dbSNP: rs768341401
Type: single nucleotide variant
Location: chr1:241512105 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 139: a β-strand

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

Disease context

fumaric aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Fumaric aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FH p.Val139Gly Uncertain significance ★★ ⚠ same residue
FH p.Val139Met Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Val139Leu Uncertain significance ★ ⚠ same residue
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>A Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>C Pathogenic ★★ same condition
FH c.1236+2T>G Pathogenic ★★ same condition
FH c.1237-1G>T 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/fh-p-val139 (accessed [today's date]).

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