Is FH p.Ile197= (c.591T>A) pathogenic?

FH p.Ile197= (c.591T>A) is classified Benign in FH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-18). Absent from gnomAD v4.1; Associated with hereditary leiomyomatosis and renal cell cancer.

What condition is associated with FH p.Ile197= (c.591T>A)?

FH p.Ile197= (c.591T>A) is associated with hereditary leiomyomatosis and renal cell cancer (ClinVar).

How common is FH p.Ile197= (c.591T>A) in the general population?

FH p.Ile197= (c.591T>A) is absent from gnomAD v4.1 (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.Ile197=

c.591T>A · VCV3773176

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 1.1	GERP -5.2, phastCons 0.99
Overall
CADD	7.408	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FH
Protein: p.Ile197=
Coding: c.591T>A
MANE Select: NM_000143
Type: single nucleotide variant
Location: chr1:241508750 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 197: 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

For Hereditary leiomyomatosis and renal cell cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Elderly

Similar variants

FH p.Ile197Leu Uncertain significance ★★ ⚠ same residue
FH p.Ile197Val Uncertain significance ★★ ⚠ same residue
FH p.Ile197Phe Likely pathogenic ★ same residue
FH c.1108+1G>A Pathogenic ★★ same condition
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1390+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1391-1G>A Pathogenic/Likely pathogenic ★★ same condition
FH c.267+1G>A Pathogenic/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-ile197 (accessed [today's date]).

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