Is FH p.Pro309= (c.927G>A) pathogenic?

FH p.Pro309= (c.927G>A) is classified Benign in FH (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-02-04). Common (popmax 10%, mid) — too common for a highly-penetrant pathogenic allele; Associated with fumaric aciduria.

What condition is associated with FH p.Pro309= (c.927G>A)?

FH p.Pro309= (c.927G>A) is associated with fumaric aciduria, hereditary leiomyomatosis and renal cell cancer, hereditary neoplastic syndrome (ClinVar).

How is Fumaric aciduria inherited?

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

FH p.Pro309=

Q: How common is FH p.Pro309= (c.927G>A) in the general population?

FH p.Pro309= (c.927G>A) is common (popmax 10%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.927G>A · rs61737760 · VCV137370

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

gnomAD v4.1

Common

common (popmax 10%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

fumaric aciduria

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 0.057	GERP -4.7, phastCons 0.97
Overall
CADD	10.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10% Middle Eastern · 608/6,052 alleles

Filtering AF 9.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.12%

Overall 2.88% 46,452/1,613,886 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	10%	10
South Asian	8.39%	12
East Asian	5.77%	17
Ashkenazi Jewishnot grpmax-eligible	5.42%	18
Remaining individualsnot grpmax-eligible	3.52%	28
Admixed American	2.59%	39
Finnishnot grpmax-eligible	2.49%	40
European (non-Finnish)	2.31%	43
African / African-American	1.88%	53
Amishnot grpmax-eligible	1.64%	61

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.Pro309=
Coding: c.927G>A
MANE Select: NM_000143
dbSNP: rs61737760
Type: single nucleotide variant
Location: chr1:241504223 (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.Pro309Arg Uncertain significance ★ ⚠ same residue
FH p.Pro309Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Pro309Ser 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

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-pro309 (accessed [today's date]).

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