Is FECH p.Pro307= (c.921A>G) pathogenic?

FECH p.Pro307= (c.921A>G) is classified Benign in FECH (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 93.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with protoporphyria, erythropoietic, 1.

What condition is associated with FECH p.Pro307= (c.921A>G)?

FECH p.Pro307= (c.921A>G) is associated with protoporphyria, erythropoietic, 1 (ClinVar).

How is Autosomal erythropoietic protoporphyria inherited?

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

FECH p.Pro307=

Q: How common is FECH p.Pro307= (c.921A>G) in the general population?

FECH p.Pro307= (c.921A>G) is common (popmax 93.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.921A>G · rs536560 · VCV255312

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 93.2%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

protoporphyria, erythropoietic, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.8
Overall
CADD	0.191	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 93.2% African / African-American · 69,959/75,040 alleles

Filtering AF 92.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 92.4%

Overall 70.2% 1,132,208/1,613,744 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	93.2%	1
South Asian	75.3%	1
Ashkenazi Jewishnot grpmax-eligible	71.1%	1
Remaining individualsnot grpmax-eligible	70.8%	1
European (non-Finnish)	69.4%	1
East Asian	67.7%	1
Middle Eastern	65.7%	2
Admixed American	64.7%	2
Finnishnot grpmax-eligible	55.6%	2
Amishnot grpmax-eligible	46.7%	2

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.Pro307=
Coding: c.921A>G
MANE Select: NM_000140
dbSNP: rs536560
Type: single nucleotide variant
Location: chr18:57554416 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 307: a β-strand

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.Pro307Leu 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-pro307 (accessed [today's date]).

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