Is FREM2 p.Phe1722fs (c.5162dup) pathogenic?

FREM2 p.Phe1722fs (c.5162dup) is classified Pathogenic/Likely pathogenic in FREM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-21). Very rare (popmax 0.00551%, nfe); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Phe1722fs (c.5162dup)?

FREM2 p.Phe1722fs (c.5162dup) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Phe1722fs (c.5162dup) in the general population?

FREM2 p.Phe1722fs (c.5162dup) is very rare (popmax 0.00551%, nfe) (gnomAD).

FREM2 p.Phe1722fs

c.5162dup · rs769926034 · VCV983512

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00551%, nfe)

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 1 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.93	GERP -0.6, phastCons 0.34
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00551% European (non-Finnish) · 65/1,179,998 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00416% 67/1,610,790 alleles · very rare exomes 61/1,458,570 · genomes 6/152,220 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00551%	18,154
Remaining individualsnot grpmax-eligible	0.0032%	31,231

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.Phe1722fs
Coding: c.5162dup
MANE Select: NM_207361
dbSNP: rs769926034
Type: Duplication
Location: chr13:38692505 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 1722: 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.Asp1100Ter Pathogenic ★★ same condition
FREM2 p.Met1985fs 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
FREM2 p.Phe2228fs Likely 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-phe1722fs (accessed [today's date]).

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