Is FH p.Arg87Cys (c.259C>T) pathogenic?

FH p.Arg87Cys (c.259C>T) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.316); Ultra-rare (popmax 0.0134%, afr); Associated with fumaric aciduria.

What condition is associated with FH p.Arg87Cys (c.259C>T)?

FH p.Arg87Cys (c.259C>T) is associated with fumaric aciduria, hereditary leiomyomatosis and renal cell cancer, hereditary neoplastic syndrome (ClinVar).

How common is FH p.Arg87Cys (c.259C>T) in the general population?

FH p.Arg87Cys (c.259C>T) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

How is Fumaric aciduria inherited?

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

What do computational predictors say about FH p.Arg87Cys (c.259C>T)?

AlphaMissense predicts likely benign (score 0.316) — an in-silico prediction, not a clinical call.

FH p.Arg87Cys

c.259C>T · rs139642944 · VCV405936

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.316 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fumaric aciduria

Computational evidence

Protein change
AlphaMissense	0.316	likely benign
REVEL	0.933	strongly pathogenic-leaning
SaProt	LLR -10.99	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% African / African-American · 10/74,888 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00124% 20/1,613,968 alleles · ultra-rare exomes 13/1,461,850 · genomes 7/152,118 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,489
Admixed American	0.00333%	30,001
European (non-Finnish)	0.000678%	147,504

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.Arg87Cys
Coding: c.259C>T
MANE Select: NM_000143
dbSNP: rs139642944
Type: single nucleotide variant
Location: chr1:241517190 (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

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

Also linked: hereditary leiomyomatosis and renal cell cancer hereditary neoplastic syndrome

For Fumaric aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FH p.Arg87Leu Uncertain significance ★★ ⚠ same residue
FH p.Arg87His Conflicting classifications of pathogenicity ★ ⚠ 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
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-arg87cys (accessed [today's date]).

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