Is FH p.Pro18Leu (c.53C>T) pathogenic?

FH p.Pro18Leu (c.53C>T) is classified Benign/Likely benign in FH (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2558); Low-frequency (popmax 1.97%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Pro18Leu (c.53C>T)?

FH p.Pro18Leu (c.53C>T) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer, fumaric aciduria (ClinVar).

How common is FH p.Pro18Leu (c.53C>T) in the general population?

FH p.Pro18Leu (c.53C>T) is low-frequency (popmax 1.97%, afr) (gnomAD).

What do computational predictors say about FH p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.2558) — an in-silico prediction, not a clinical call.

FH p.Pro18Leu

c.53C>T · rs201887750 · VCV134413

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.2558 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.97%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2558	likely benign
REVEL	0.39	indeterminate
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.72	GERP 0.51, phastCons 0.012
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	15.96	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 1.97% African / African-American · 1,441/73,048 alleles

Filtering AF 1.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.85%

Overall 0.104% 1,614/1,547,802 alleles · low-frequency exomes 767/1,395,434 · genomes 847/152,368 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.97%	51
Admixed American	0.145%	688
Remaining individualsnot grpmax-eligible	0.144%	696
Middle Eastern	0.0455%	2,197
European (non-Finnish)	0.00096%	104,213

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.Pro18Leu
Coding: c.53C>T
MANE Select: NM_000143
dbSNP: rs201887750
Type: single nucleotide variant
Location: chr1:241519670 (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.Pro18Ala Uncertain significance ★★ ⚠ same residue
FH p.Pro18Ser Uncertain significance ★★ ⚠ same residue
FH p.Pro18= 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

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-pro18leu (accessed [today's date]).

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