Is FECH p.Tyr194fs (c.580_584del) pathogenic?

FECH p.Tyr194fs (c.580584del) is classified Pathogenic in FECH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-20). Very rare (popmax 8.47e-05%, nfe); Associated with protoporphyria, erythropoietic, 1.

What condition is associated with FECH p.Tyr194fs (c.580_584del)?

FECH p.Tyr194fs (c.580_584del) is associated with protoporphyria, erythropoietic, 1 (ClinVar).

How common is FECH p.Tyr194fs (c.580_584del) in the general population?

FECH p.Tyr194fs (c.580_584del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Autosomal erythropoietic protoporphyria inherited?

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

FECH p.Tyr194fs

c.580_584del · rs786205248 · VCV560

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

protoporphyria, erythropoietic, 1

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 5 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.2	GERP 0.99, phastCons 1
Overall
CADD	35.0	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 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 0.000657% 1/152,228 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: FECH
Protein: p.Tyr194fs
Coding: c.580_584del
MANE Select: NM_000140
dbSNP: rs786205248
Type: Deletion
Location: chr18:57566461 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB

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

Disease context

protoporphyria, erythropoietic, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal erythropoietic protoporphyria (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

FECH p.Ala14fs Pathogenic ★★ same condition
FECH p.Lys379fs Pathogenic/Likely pathogenic ★★ same condition
FECH p.Gln122fs Likely pathogenic ★ same condition
FECH p.Ile134fs Pathogenic ★ same condition
FECH p.Tyr194Cys Uncertain significance ★ ⚠ same residue
FECH c.1137+3A>G Pathogenic/Likely pathogenic ★★ same condition
FECH c.314+2T>G Pathogenic/Likely pathogenic ★★ same condition
FECH c.463+1G>C 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/fech-p-tyr194fs (accessed [today's date]).

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