Is FREM2 p.Pro28= (c.84C>G) pathogenic?

FREM2 p.Pro28= (c.84C>G) is classified Benign/Likely benign in FREM2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Rare (popmax 0.845%, afr); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Pro28= (c.84C>G)?

FREM2 p.Pro28= (c.84C>G) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Pro28= (c.84C>G) in the general population?

FREM2 p.Pro28= (c.84C>G) is rare (popmax 0.845%, afr) (gnomAD).

FREM2 p.Pro28=

c.84C>G · rs141718695 · VCV193533

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.845%, afr)

Conditions

Fraser syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -4.2
Overall
CADD	3.823	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.845% African / African-American · 633/74,872 alleles

Filtering AF 0.791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.769%

Overall 0.141% 2,262/1,601,794 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.845%	118
Middle Eastern	0.546%	183
Admixed American	0.427%	234
Remaining individualsnot grpmax-eligible	0.239%	419
South Asian	0.204%	491
European (non-Finnish)	0.0862%	1,160
Ashkenazi Jewishnot grpmax-eligible	0.00683%	14,643
Finnishnot grpmax-eligible	0.00162%	61,736

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.Pro28=
Coding: c.84C>G
MANE Select: NM_207361
dbSNP: rs141718695
Type: single nucleotide variant
Location: chr13:38687428 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)

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.Pro28Arg Uncertain significance ★ ⚠ same residue
FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Arg638Ter Likely pathogenic ★★ same condition
FREM2 p.Arg736Ter Pathogenic ★★ same condition
FREM2 p.Arg809Ter Pathogenic ★★ same condition
FREM2 p.Gln1051Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Gln717Ter Likely pathogenic ★★ same condition
FREM2 p.Ala1659Thr 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-pro28 (accessed [today's date]).

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