Is FECH p.Ala14fs (c.40del) pathogenic?

FECH p.Ala14fs (c.40del) is classified Pathogenic in FECH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). Very rare (popmax 0.00298%, nfe); Associated with protoporphyria, erythropoietic, 1.

What condition is associated with FECH p.Ala14fs (c.40del)?

FECH p.Ala14fs (c.40del) is associated with protoporphyria, erythropoietic, 1 (ClinVar).

How common is FECH p.Ala14fs (c.40del) in the general population?

FECH p.Ala14fs (c.40del) is very rare (popmax 0.00298%, 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.Ala14fs

c.40del · rs1171981319 · VCV1805745

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00298%, 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 1 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.6	GERP -0.76, phastCons 0.91

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00298% European (non-Finnish) · 34/1,141,570 alleles

Filtering AF 0.00214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00189%

Overall 0.0023% 35/1,521,748 alleles · very rare exomes 35/1,369,478 · genomes 0/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00298%	33,576
Remaining individualsnot grpmax-eligible	0.00169%	59,338

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.Ala14fs
Coding: c.40del
MANE Select: NM_000140
dbSNP: rs1171981319
Type: Deletion
Location: chr18:57586581 (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.Lys379fs Pathogenic/Likely pathogenic ★★ same condition
FECH p.Tyr194fs Pathogenic ★★ same condition
FECH p.Gln122fs Likely pathogenic ★ same condition
FECH p.Ile134fs 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

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-ala14fs (accessed [today's date]).

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