Is FECH p.Phe417Ser (c.1250T>C) pathogenic?

FECH p.Phe417Ser (c.1250T>C) is classified Pathogenic in FECH (ClinVar, No assertion criteria, 1 submitter; last evaluated 1992-06-01). AlphaMissense: likely pathogenic (0.9455); Absent from gnomAD v4.1; Associated with protoporphyria, erythropoietic, 1.

What condition is associated with FECH p.Phe417Ser (c.1250T>C)?

FECH p.Phe417Ser (c.1250T>C) is associated with protoporphyria, erythropoietic, 1 (ClinVar).

How common is FECH p.Phe417Ser (c.1250T>C) in the general population?

FECH p.Phe417Ser (c.1250T>C) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal erythropoietic protoporphyria inherited?

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

What do computational predictors say about FECH p.Phe417Ser (c.1250T>C)?

AlphaMissense predicts likely pathogenic (score 0.9455) — an in-silico prediction, not a clinical call.

FECH p.Phe417Ser

c.1250T>C · rs118204039 · VCV551

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9455 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

protoporphyria, erythropoietic, 1

Computational evidence

Protein change
AlphaMissense	0.9455	likely pathogenic ✓ concordant with ClinVar
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -13.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FECH
Protein: p.Phe417Ser
Coding: c.1250T>C
MANE Select: NM_000140
dbSNP: rs118204039
Type: single nucleotide variant
Location: chr18:57550734 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 417: a UniProt-annotated variant site (in epp1; reduced activity); a UniProt-annotated variant site (in epp1; enzyme totally inactive); 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 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.Arg115Ter Pathogenic/Likely pathogenic ★★ same condition
FECH p.Arg96Ter Pathogenic/Likely pathogenic ★★ same condition
FECH p.Asp274Asn Pathogenic ★★ same condition
FECH p.Cys406Tyr 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-phe417ser (accessed [today's date]).

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