Is FECH p.Pro334Leu (c.1001C>T) pathogenic?

FECH p.Pro334Leu (c.1001C>T) is classified Pathogenic/Likely pathogenic in FECH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-19). AlphaMissense: likely pathogenic (0.9861); Ultra-rare (popmax 0.0155%, nfe); Associated with protoporphyria, erythropoietic, 1.

What condition is associated with FECH p.Pro334Leu (c.1001C>T)?

FECH p.Pro334Leu (c.1001C>T) is associated with protoporphyria, erythropoietic, 1 (ClinVar).

How common is FECH p.Pro334Leu (c.1001C>T) in the general population?

FECH p.Pro334Leu (c.1001C>T) is ultra-rare (popmax 0.0155%, nfe) (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.Pro334Leu (c.1001C>T)?

AlphaMissense predicts likely pathogenic (score 0.9861) — an in-silico prediction, not a clinical call.

FECH p.Pro334Leu

c.1001C>T · rs150146721 · VCV375409

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

protoporphyria, erythropoietic, 1

Computational evidence

Protein change
AlphaMissense	0.9861	likely pathogenic ✓ concordant with ClinVar · top 8% in FECH
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -11.73	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	32.0	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 0.0155% European (non-Finnish) · 183/1,180,034 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0124% 200/1,614,156 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,683
European (non-Finnish)grpmax	0.0155%	6,448
Finnishnot grpmax-eligible	0.00312%	32,011
African / African-American	0.00267%	37,517
East Asian	0.00223%	44,882
South Asian	0.0011%	91,076

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro334Leu
Coding: c.1001C>T
MANE Select: NM_000140
dbSNP: rs150146721
Type: single nucleotide variant
Location: chr18:57554336 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 334: a UniProt-annotated variant site (in epp1; enzyme retains 19% of activity)

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

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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-pro334leu (accessed [today's date]).

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