Is FH p.Arg43Ter (c.127C>T) pathogenic?

FH p.Arg43Ter (c.127C>T) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-08). Very rare (popmax 0.000262%, nfe); Associated with hereditary leiomyomatosis and renal cell cancer.

What condition is associated with FH p.Arg43Ter (c.127C>T)?

FH p.Arg43Ter (c.127C>T) is associated with hereditary leiomyomatosis and renal cell cancer, fumaric aciduria, hereditary neoplastic syndrome (ClinVar).

How common is FH p.Arg43Ter (c.127C>T) in the general population?

FH p.Arg43Ter (c.127C>T) is very rare (popmax 0.000262%, nfe) (gnomAD).

How is Hereditary leiomyomatosis and renal cell cancer inherited?

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

FH p.Arg43Ter

c.127C>T · rs200496951 · VCV644260

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000262%, nfe)

Conditions

hereditary leiomyomatosis and renal cell cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.65	GERP -0.93, phastCons 0.11
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000262% European (non-Finnish) · 3/1,146,316 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000215% 3/1,395,196 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: FH
Protein: p.Arg43Ter
Coding: c.127C>T
MANE Select: NM_000143
dbSNP: rs200496951
Type: single nucleotide variant
Location: chr1:241519596 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB

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

Disease context

hereditary leiomyomatosis and renal cell cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: fumaric aciduria hereditary neoplastic syndrome

For Hereditary leiomyomatosis and renal cell cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Elderly

Similar variants

FH p.Arg43Gly Uncertain significance ★★ ⚠ same residue
FH p.Arg43Pro Uncertain significance ★ ⚠ same residue
FH p.Arg43Leu Uncertain significance ★ ⚠ same residue
FH c.1108+1G>A Pathogenic ★★ same condition
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

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-arg43ter (accessed [today's date]).

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