Is FAH p.Ser366del (c.1097_1099del) pathogenic?

FAH p.Ser366del (c.10971099del) is classified Conflicting classifications of pathogenicity in FAH (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-15). Very rare (popmax 0.00153%, nfe); Associated with tyrosinemia type I.

What condition is associated with FAH p.Ser366del (c.1097_1099del)?

FAH p.Ser366del (c.1097_1099del) is associated with tyrosinemia type I (ClinVar).

How common is FAH p.Ser366del (c.1097_1099del) in the general population?

FAH p.Ser366del (c.1097_1099del) is very rare (popmax 0.00153%, nfe) (gnomAD).

How is Tyrosinemia type 1 inherited?

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

FAH p.Ser366del

c.1097_1099del · rs1342338851 · VCV2051160

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

tyrosinemia type I

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.1	GERP 1.5, phastCons 1
Overall
CADD	16.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,850 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,613,794 alleles · very rare exomes 16/1,461,572 · genomes 2/152,222 · 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: FAH
Protein: p.Ser366del
Coding: c.1097_1099del
MANE Select: NM_000137
dbSNP: rs1342338851
Type: Deletion
Location: chr15:80181074 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 98.06 · 8 PDB
Residue 366: a UniProt-annotated variant site (in tyrsn1)

Full FAH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tyrosinemia type I — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Tyrosinemia type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

FAH p.Ser366Leu Uncertain significance ★★ ⚠ same residue
FAH p.Ser366= Likely benign ★ same residue
FAH c.548_553+20del Pathogenic/Likely pathogenic ★★ same condition
FAH p.Ala203fs Pathogenic/Likely pathogenic ★★ same condition
FAH p.Asn146fs Pathogenic/Likely pathogenic ★★ same condition
FAH p.Gln397fs Likely pathogenic ★★ same condition
FAH p.Gln64fs Pathogenic ★★ same condition
FAH p.Gly337_Cys338insTer 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/fah-p-ser366del (accessed [today's date]).

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