Is FH p.Pro18Ser (c.52C>T) pathogenic?

FH p.Pro18Ser (c.52C>T) is classified Uncertain significance in FH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-09). AlphaMissense: likely benign (0.083); Very rare (popmax 0.00137%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Pro18Ser (c.52C>T)?

FH p.Pro18Ser (c.52C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FH p.Pro18Ser (c.52C>T) in the general population?

FH p.Pro18Ser (c.52C>T) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about FH p.Pro18Ser (c.52C>T)?

AlphaMissense predicts likely benign (score 0.083) — an in-silico prediction, not a clinical call.

FH p.Pro18Ser

c.52C>T · VCV3343365

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.083	likely benign
REVEL	0.354	indeterminate
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 1.9, phastCons 0.021
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	12.73	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00137% African / African-American · 1/73,048 alleles

Overall 6.46e-05% 1/1,547,704 alleles · very rare exomes 1/1,395,326 · genomes 0/152,378 · 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.Pro18Ser
Coding: c.52C>T
MANE Select: NM_000143
Type: single nucleotide variant
Location: chr1:241519671 (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.Pro18Ala Uncertain significance ★★ ⚠ same residue
FH p.Pro18= Likely benign ★★ same residue
FH p.Pro18Leu Benign/Likely benign ★★ 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
FH c.1236+2T>G Pathogenic ★★ same condition
FH c.1237-1G>T 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-pro18ser (accessed [today's date]).

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