Is FECH p.Glu121Gly (c.362A>G) pathogenic?

FECH p.Glu121Gly (c.362A>G) is classified Conflicting classifications of pathogenicity in FECH (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.1981); Rare (popmax 0.132%, mid); Associated with protoporphyria, erythropoietic, 1.

What condition is associated with FECH p.Glu121Gly (c.362A>G)?

FECH p.Glu121Gly (c.362A>G) is associated with protoporphyria, erythropoietic, 1 (ClinVar).

How common is FECH p.Glu121Gly (c.362A>G) in the general population?

FECH p.Glu121Gly (c.362A>G) is rare (popmax 0.132%, 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.Glu121Gly (c.362A>G)?

AlphaMissense predicts likely benign (score 0.1981) — an in-silico prediction, not a clinical call.

FECH p.Glu121Gly

c.362A>G · rs141813907 · VCV327433

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1981 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

protoporphyria, erythropoietic, 1

Computational evidence

Protein change
AlphaMissense	0.1981	likely benign
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -12.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	24.8	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 0.132% Middle Eastern · 8/6,062 alleles

Filtering AF 0.0656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0518%

Overall 0.0463% 748/1,613,988 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	758
European (non-Finnish)	0.0568%	1,761
Remaining individualsnot grpmax-eligible	0.0544%	1,838
Admixed American	0.02%	4,999
African / African-American	0.016%	6,250
South Asian	0.00988%	10,118
Finnishnot grpmax-eligible	0.00469%	21,334

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.Glu121Gly
Coding: c.362A>G
MANE Select: NM_000140
dbSNP: rs141813907
Type: single nucleotide variant
Location: chr18:57571493 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 121: 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-glu121gly (accessed [today's date]).

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