Is FH p.Pro503fs (c.1506dup) pathogenic?

FH p.Pro503fs (c.1506dup) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2021-01-13). Absent from gnomAD; Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Pro503fs (c.1506dup)?

FH p.Pro503fs (c.1506dup) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer (ClinVar).

How common is FH p.Pro503fs (c.1506dup) in the general population?

FH p.Pro503fs (c.1506dup) is absent from gnomAD (gnomAD).

FH p.Pro503fs

c.1506dup · rs886041202 · VCV279808

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FH
Protein: p.Pro503fs
Coding: c.1506dup
MANE Select: NM_000143
dbSNP: rs886041202
Type: Duplication
Location: chr1:241497854 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 503: an α-helix

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

Also linked: hereditary leiomyomatosis and renal cell cancer

Similar variants

FH p.Pro503Arg Uncertain significance ★★ ⚠ same residue
FH p.Pro503= Likely benign ★ same residue
FH p.Ala468fs Pathogenic ★★ same condition
FH p.Asn107Ter Pathogenic ★★ same condition
FH p.Asn446fs Pathogenic ★★ same condition
FH p.Gly275fs Pathogenic ★★ same condition
FH p.Ile81fs Pathogenic ★★ same condition
FH p.Leu353fs 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-pro503fs (accessed [today's date]).

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