Is FH p.Ser222Pro (c.664T>C) pathogenic?

FH p.Ser222Pro (c.664T>C) is classified Likely pathogenic in FH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-02). AlphaMissense: likely pathogenic (0.9585); Absent from gnomAD v4.1; Associated with fumaric aciduria.

What condition is associated with FH p.Ser222Pro (c.664T>C)?

FH p.Ser222Pro (c.664T>C) is associated with fumaric aciduria (ClinVar).

How common is FH p.Ser222Pro (c.664T>C) in the general population?

FH p.Ser222Pro (c.664T>C) is absent from gnomAD v4.1 (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.Ser222Pro (c.664T>C)?

AlphaMissense predicts likely pathogenic (score 0.9585) — an in-silico prediction, not a clinical call.

FH p.Ser222Pro

c.664T>C · rs1448268784 · VCV1320066

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9585 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fumaric aciduria

Computational evidence

Protein change
AlphaMissense	0.9585	likely pathogenic ✓ concordant with ClinVar
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -14.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	23.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FH
Protein: p.Ser222Pro
Coding: c.664T>C
MANE Select: NM_000143
dbSNP: rs1448268784
Type: single nucleotide variant
Location: chr1:241508677 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 222: an α-helix

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

For Fumaric aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FH p.Ser222Thr Uncertain significance ★★ ⚠ same residue
FH p.Ser222Phe Uncertain significance ★ ⚠ same residue
FH p.Ser222= Likely benign ★ same residue
FH c.1390+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1391-1G>C Pathogenic ★★ same condition
FH c.1391-1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1391-2A>T Pathogenic/Likely pathogenic ★★ same condition
FH c.378+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-ser222pro (accessed [today's date]).

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