Is FH p.Pro304= (c.912T>C) pathogenic?

FH p.Pro304= (c.912T>C) is classified Likely benign in FH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-24). Very rare (popmax 6.2e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Pro304= (c.912T>C)?

FH p.Pro304= (c.912T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FH p.Pro304= (c.912T>C) in the general population?

FH p.Pro304= (c.912T>C) is very rare (popmax 6.2e-05%) (gnomAD).

FH p.Pro304=

c.912T>C · rs1573880603 · VCV1152883

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

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 1.4	GERP -2.4, phastCons 1
Overall
CADD	8.509	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,134 alleles · very rare exomes 1/1,461,762 · genomes 0/152,372 · joint denominator

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.Pro304=
Coding: c.912T>C
MANE Select: NM_000143
dbSNP: rs1573880603
Type: single nucleotide variant
Location: chr1:241504238 (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

Similar variants

FH p.Pro304Ser Uncertain significance ★★ ⚠ same residue
FH p.Pro304Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Pro304Leu Uncertain significance ★ ⚠ same residue
FH p.Pro304fs Pathogenic ★★ same residue
FH p.Pro304Ala Uncertain significance ★ ⚠ same residue
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-pro304 (accessed [today's date]).

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