Is FREM2 p.Phe2228fs (c.6680_6681dup) pathogenic?

FREM2 p.Phe2228fs (c.66806681dup) is classified Likely pathogenic in FREM2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-06-30). No gnomAD frequency available for this variant; Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Phe2228fs (c.6680_6681dup)?

FREM2 p.Phe2228fs (c.6680_6681dup) is associated with Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Phe2228fs (c.6680_6681dup) in the general population?

FREM2 p.Phe2228fs (c.6680_6681dup) is no gnomAD frequency available for this variant (gnomAD).

FREM2 p.Phe2228fs

c.6680_6681dup · rs2541488826 · VCV1723213

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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	predicted	premature termination codon in exon 10 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.4	GERP -5.2

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FREM2
Protein: p.Phe2228fs
Coding: c.6680_6681dup
MANE Select: NM_207361
dbSNP: rs2541488826
Type: Duplication
Location: chr13:38851044 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2228: 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

Similar variants

FREM2 p.Asp1100Ter Pathogenic ★★ same condition
FREM2 p.Met1985fs Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Phe1722fs Pathogenic/Likely pathogenic ★★ same condition
FREM2 c.7520-5dup Benign/Likely benign ★★ same condition
FREM2 c.7520-6_7520-5dup Benign ★★ same condition
FREM2 p.Val2516fs Likely pathogenic ★ same condition
FREM2 c.8176+2dup Conflicting classifications of pathogenicity ★ same condition
FREM2 p.Lys3138fs Uncertain significance ★ 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-phe2228fs (accessed [today's date]).

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