Is FH p.Cys434= (c.1302C>T) pathogenic?

FH p.Cys434= (c.1302C>T) is classified Benign in FH (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-04). Common (popmax 10.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Cys434= (c.1302C>T)?

FH p.Cys434= (c.1302C>T) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer, fumaric aciduria (ClinVar).

FH p.Cys434=

Q: How common is FH p.Cys434= (c.1302C>T) in the general population?

FH p.Cys434= (c.1302C>T) is common (popmax 10.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1302C>T · rs2070080 · VCV137372

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Common

common (popmax 10.6%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.4	GERP -5.2
Overall
CADD	0.927	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.6% African / African-American · 7,893/74,506 alleles

Filtering AF 10.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.3%

Overall 0.557% 8,961/1,608,838 alleles · common exomes 4,522/1,458,070 · genomes 4,439/150,768 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.6%	9
Remaining individualsnot grpmax-eligible	0.662%	151
Admixed American	0.622%	161
Middle Eastern	0.348%	287
European (non-Finnish)	0.0212%	4,708
South Asian	0.0121%	8,270
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,422
East Asian	0.00224%	44,634

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.Cys434=
Coding: c.1302C>T
MANE Select: NM_000143
dbSNP: rs2070080
Type: single nucleotide variant
Location: chr1:241500525 (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: hereditary leiomyomatosis and renal cell cancer fumaric aciduria

Similar variants

FH p.Cys434Arg Pathogenic/Likely pathogenic ★★ same residue
FH p.Cys434Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Cys434Phe Likely pathogenic ★ same residue
FH p.Cys434Ter Likely pathogenic ★ 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

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-cys434 (accessed [today's date]).

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