Is FECH p.Met267Ile (c.801G>A) pathogenic?

FECH p.Met267Ile (c.801G>A) is classified Uncertain significance in FECH (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-08-04). AlphaMissense: ambiguous (0.5203); Rare (popmax 0.563%, mid); Associated with protoporphyria, erythropoietic, 1.

What condition is associated with FECH p.Met267Ile (c.801G>A)?

FECH p.Met267Ile (c.801G>A) is associated with protoporphyria, erythropoietic, 1 (ClinVar).

How common is FECH p.Met267Ile (c.801G>A) in the general population?

FECH p.Met267Ile (c.801G>A) is rare (popmax 0.563%, mid) (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.Met267Ile (c.801G>A)?

AlphaMissense predicts ambiguous (score 0.5203) — an in-silico prediction, not a clinical call.

FECH p.Met267Ile

c.801G>A · rs118204037 · VCV549

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.5203 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.563%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

protoporphyria, erythropoietic, 1

Computational evidence

Protein change
AlphaMissense	0.5203	ambiguous
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -10.00	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	24.1	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

Grpmax group 0.563% Middle Eastern · 34/6,042 alleles

Filtering AF 0.414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.363%

Overall 0.124% 1,994/1,602,630 alleles · rare exomes 1,830/1,450,392 · genomes 164/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.563%	178
Finnishnot grpmax-eligible	0.156%	639
European (non-Finnish)	0.145%	691
Remaining individualsnot grpmax-eligible	0.113%	887
Admixed American	0.0733%	1,364
South Asian	0.0429%	2,329
African / African-American	0.0188%	5,332
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,534

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.Met267Ile
Coding: c.801G>A
MANE Select: NM_000140
dbSNP: rs118204037
Type: single nucleotide variant
Location: chr18:57559148 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 267: a UniProt-annotated variant site (in epp1; unchanged activity; but increased thermolability); 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.Met267Thr 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
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

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-met267ile (accessed [today's date]).

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