Is FH p.Ser11Pro (c.31T>C) pathogenic?

FH p.Ser11Pro (c.31T>C) is classified Uncertain significance in FH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-20). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.00197%, amr); Associated with fumaric aciduria.

What condition is associated with FH p.Ser11Pro (c.31T>C)?

FH p.Ser11Pro (c.31T>C) is associated with fumaric aciduria, hereditary leiomyomatosis and renal cell cancer (ClinVar).

How common is FH p.Ser11Pro (c.31T>C) in the general population?

FH p.Ser11Pro (c.31T>C) is very rare (popmax 0.00197%, amr) (gnomAD).

How is Fumaric aciduria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FH p.Ser11Pro (c.31T>C)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

FH p.Ser11Pro

c.31T>C · rs1660323255 · VCV1429906

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00197%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

fumaric aciduria

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.73	GERP -2.2, phastCons 0.001
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	14.79	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 0.00197% Admixed American · 1/50,854 alleles

Overall 6.47e-05% 1/1,546,624 alleles · very rare exomes 0/1,394,548 · genomes 1/152,076 · 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.Ser11Pro
Coding: c.31T>C
MANE Select: NM_000143
dbSNP: rs1660323255
Type: single nucleotide variant
Location: chr1:241519692 (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

fumaric aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary leiomyomatosis and renal cell cancer

For Fumaric aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FH p.Ser11= Benign/Likely benign ★★ same residue
FH p.Ser11Ter Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Ser11Leu Uncertain significance ★★ ⚠ same residue
FH p.Ser11Trp Uncertain significance ★★ ⚠ same residue
FH c.1108+1G>A Pathogenic ★★ same condition
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1390+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1391-1G>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-ser11pro (accessed [today's date]).

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