Is FREM2 p.Arg3142fs (c.9424del) pathogenic?

FREM2 p.Arg3142fs (c.9424del) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-03). Very rare (popmax 0.00446%, eas); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Arg3142fs (c.9424del)?

FREM2 p.Arg3142fs (c.9424del) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Arg3142fs (c.9424del) in the general population?

FREM2 p.Arg3142fs (c.9424del) is very rare (popmax 0.00446%, eas) (gnomAD).

FREM2 p.Arg3142fs

c.9424del · VCV3576249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Fraser syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (24 of 24) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.054	GERP 0.21

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,866 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,874 alleles · very rare

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: FREM2
Protein: p.Arg3142fs
Coding: c.9424del
MANE Select: NM_207361
Type: Deletion
Location: chr13:38880701 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 3142: the 'disordered' region; a UniProt-annotated variant site (in cryptop)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fraser syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated cryptophthalmia

Similar variants

FREM2 p.Ala1996fs Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Gln1190fs Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.His945fs Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Leu2493fs Pathogenic/Likely pathogenic ★★ same condition
FREM2 c.7520-5del Benign/Likely benign ★★ same condition
FREM2 p.Asn959fs Likely pathogenic ★ same condition
FREM2 p.Asp2086fs Likely pathogenic ★ same condition
FREM2 p.Asp423fs 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/frem2-p-arg3142fs (accessed [today's date]).

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