Is FH p.Lys447= (c.1341G>A) pathogenic?

FH p.Lys447= (c.1341G>A) is classified Benign/Likely benign in FH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-22). Very rare (popmax 0.00333%, amr); Associated with hereditary leiomyomatosis and renal cell cancer.

How common is FH p.Lys447= (c.1341G>A) in the general population?

FH p.Lys447= (c.1341G>A) is very rare (popmax 0.00333%, amr) (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.Lys447=

Q: What condition is associated with FH p.Lys447= (c.1341G>A)?

FH p.Lys447= (c.1341G>A) is associated with hereditary leiomyomatosis and renal cell cancer, hereditary neoplastic syndrome (ClinVar).

c.1341G>A · rs748363858 · VCV702418

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

hereditary leiomyomatosis and renal cell cancer

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 2.5	GERP -0.091, phastCons 1
Overall
CADD	10.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,986 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,613,876 alleles · very rare exomes 5/1,461,794 · genomes 1/152,082 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,993
European (non-Finnish)	0.000339%	294,993

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.Lys447=
Coding: c.1341G>A
MANE Select: NM_000143
dbSNP: rs748363858
Type: single nucleotide variant
Location: chr1:241500486 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 447: an α-helix

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: hereditary neoplastic syndrome

For Hereditary leiomyomatosis and renal cell cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Elderly

Similar variants

FH p.Lys447Ter Pathogenic ★★ same residue
FH p.Lys447Arg Uncertain significance ★★ ⚠ same residue
FH p.Lys447Gln 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-lys447 (accessed [today's date]).

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