Is FH p.Arg3Ter (c.7C>T) pathogenic?

FH p.Arg3Ter (c.7C>T) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-27). Very rare (popmax 0.000175%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Arg3Ter (c.7C>T)?

FH p.Arg3Ter (c.7C>T) is associated with hereditary neoplastic syndrome, fumaric aciduria (ClinVar).

How common is FH p.Arg3Ter (c.7C>T) in the general population?

FH p.Arg3Ter (c.7C>T) is very rare (popmax 0.000175%, nfe) (gnomAD).

FH p.Arg3Ter

c.7C>T · rs202166344 · VCV214391

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000175%, nfe)

Conditions

hereditary neoplastic syndrome

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 5.3	GERP 1, phastCons 0.98
Overall
CADD	41.0	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 0.000175% European (non-Finnish) · 2/1,143,334 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000194% 3/1,543,802 alleles · very rare exomes 3/1,391,454 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00168%	59,606
European (non-Finnish)grpmax	0.000175%	571,667

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg3Ter
Coding: c.7C>T
MANE Select: NM_000143
dbSNP: rs202166344
Type: single nucleotide variant
Location: chr1:241519716 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: fumaric aciduria

Similar variants

FH p.Arg3Gln Uncertain significance ★★ ⚠ same residue
FH p.Arg3Pro Uncertain significance ★★ ⚠ same residue
FH p.Arg3Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Arg3= Likely benign ★ same residue
FH p.Arg3fs 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

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-arg3ter (accessed [today's date]).

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