Is FAH p.Pro261fs (c.780_781del) pathogenic?

FAH p.Pro261fs (c.780781del) is classified Pathogenic/Likely pathogenic in FAH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-23). Very rare (popmax 0.00133%, afr); Associated with tyrosinemia type I.

What condition is associated with FAH p.Pro261fs (c.780_781del)?

FAH p.Pro261fs (c.780_781del) is associated with tyrosinemia type I (ClinVar).

How common is FAH p.Pro261fs (c.780_781del) in the general population?

FAH p.Pro261fs (c.780_781del) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Tyrosinemia type 1 inherited?

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

FAH p.Pro261fs

c.780_781del · rs1057517436 · VCV371645

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

tyrosinemia type I

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.2	GERP 0.27, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,940 alleles

Overall 0.000657% 1/152,232 alleles · very rare

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.Pro261fs
Coding: c.780_781del
MANE Select: NM_000137
dbSNP: rs1057517436
Type: Microsatellite
Location: chr15:80173083 (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 261: 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.Pro261Leu Pathogenic/Likely pathogenic ★★ same residue
FAH p.Pro261= Likely benign ★ same residue
FAH c.553+2_553+3del Likely pathogenic ★★ same condition
FAH p.Cys315fs Likely pathogenic ★ same condition
FAH p.Met270fs Likely pathogenic ★ same condition
FAH p.Ser334fs Likely pathogenic ★ same condition
FAH c.707-7_707-5del Conflicting classifications of pathogenicity ★ same condition
FAH c.82-5_82-3del Likely benign ★ 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-pro261fs (accessed [today's date]).

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