Is FECH p.Ser254fs (c.757_761del) pathogenic?

FECH p.Ser254fs (c.757761del) is classified Pathogenic in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). Very rare (popmax 0.00401%, afr); Associated with protoporphyria, erythropoietic, 1.

What condition is associated with FECH p.Ser254fs (c.757_761del)?

FECH p.Ser254fs (c.757_761del) is associated with protoporphyria, erythropoietic, 1 (ClinVar).

How common is FECH p.Ser254fs (c.757_761del) in the general population?

FECH p.Ser254fs (c.757_761del) is very rare (popmax 0.00401%, afr) (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.Ser254fs

c.757_761del · VCV3393342

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

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 7 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.3	GERP -0.31
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 0.00401% African / African-American · 3/74,856 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,540 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,952
European (non-Finnish)	8.48e-05%	1,179,722

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.Ser254fs
Coding: c.757_761del
MANE Select: NM_000140
Type: Microsatellite
Location: chr18:57559188 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 254: an α-helix

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.Trp301fs Pathogenic ★★ same condition
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
FECH c.598+1G>T Pathogenic ★★ same condition
FECH p.Ala14fs Pathogenic ★★ same condition
FECH p.Arg115Ter Pathogenic/Likely pathogenic ★★ same condition
FECH p.Arg96Ter 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/fech-p-ser254fs (accessed [today's date]).

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