Is FH p.Pro304Arg (c.911C>G) pathogenic?

FH p.Pro304Arg (c.911C>G) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.3073); Rare (popmax 0.152%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Pro304Arg (c.911C>G)?

FH p.Pro304Arg (c.911C>G) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer, fumaric aciduria (ClinVar).

How common is FH p.Pro304Arg (c.911C>G) in the general population?

FH p.Pro304Arg (c.911C>G) is rare (popmax 0.152%, sas) (gnomAD).

What do computational predictors say about FH p.Pro304Arg (c.911C>G)?

AlphaMissense predicts likely benign (score 0.3073) — an in-silico prediction, not a clinical call.

FH p.Pro304Arg

c.911C>G · rs200491078 · VCV460381

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3073 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.152%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3073	likely benign
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -10.87	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.152% South Asian · 138/91,066 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.00936% 151/1,613,826 alleles · rare exomes 143/1,461,744 · genomes 8/152,082 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.152%	660
Middle Eastern	0.033%	3,028
Remaining individualsnot grpmax-eligible	0.016%	6,248
European (non-Finnish)	8.47e-05%	1,179,974

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.Pro304Arg
Coding: c.911C>G
MANE Select: NM_000143
dbSNP: rs200491078
Type: single nucleotide variant
Location: chr1:241504239 (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

Also linked: hereditary leiomyomatosis and renal cell cancer fumaric aciduria

Similar variants

FH p.Pro304Ser Uncertain significance ★★ ⚠ same residue
FH p.Pro304= Likely benign ★★ 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>A Pathogenic ★★ same condition
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+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-pro304arg (accessed [today's date]).

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