Is FH p.Pro26= (c.78C>T) pathogenic?

FH p.Pro26= (c.78C>T) is classified Benign/Likely benign in FH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-24). Very rare (popmax 0.00245%, eas); Associated with hereditary leiomyomatosis and renal cell cancer.

What condition is associated with FH p.Pro26= (c.78C>T)?

FH p.Pro26= (c.78C>T) is associated with hereditary leiomyomatosis and renal cell cancer, hereditary neoplastic syndrome (ClinVar).

How common is FH p.Pro26= (c.78C>T) in the general population?

FH p.Pro26= (c.78C>T) is very rare (popmax 0.00245%, eas) (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.Pro26=

c.78C>T · rs1029677665 · VCV514503

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00245%, eas)

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 -0.53	GERP -3.1, phastCons 0.004
Overall
CADD	1.462	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00245% East Asian · 1/40,890 alleles

Filtering AF 0.000188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000124%

Overall 0.000581% 9/1,548,004 alleles · very rare exomes 9/1,395,640 · genomes 0/152,364 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00245%	40,890
Admixed American	0.00196%	50,968
South Asian	0.00119%	83,898
European (non-Finnish)	0.000523%	191,083

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.Pro26=
Coding: c.78C>T
MANE Select: NM_000143
dbSNP: rs1029677665
Type: single nucleotide variant
Location: chr1:241519645 (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 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.Pro26Leu Benign/Likely benign ★★ 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
FH c.1390+1G>T 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-pro26 (accessed [today's date]).

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