Is FECH p.Leu72fs (c.215dup) pathogenic?

FECH p.Leu72fs (c.215dup) is classified Pathogenic in FECH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-15). Very rare (popmax 0.00167%, amr).

How common is FECH p.Leu72fs (c.215dup) in the general population?

FECH p.Leu72fs (c.215dup) is very rare (popmax 0.00167%, amr) (gnomAD).

FECH p.Leu72fs

c.215dup · rs773486338 · VCV2683631

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.92	GERP -3.8, phastCons 0.01

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,034 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,158 alleles · very rare exomes 4/1,461,824 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,034
European (non-Finnish)	0.000254%	393,331

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.Leu72fs
Coding: c.215dup
MANE Select: NM_000140
dbSNP: rs773486338
Type: Duplication
Location: chr18:57573344 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 72: a β-strand

Full FECH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FECH p.Ile319fs Pathogenic ★★ same type
FECH p.Thr69fs Pathogenic ★★ same type
FECH c.598+1dup Likely pathogenic ★ same type
FECH p.Thr338fs Pathogenic ★ same type
FECH p.Tyr293Ter Likely pathogenic ★ same type
FECH p.Val85fs Pathogenic ★ same type
FECH c.804+217dup Benign ★ same type
FECH p.Glu351fs Pathogenic same type

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-leu72fs (accessed [today's date]).

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