Is FREM2 p.Pro397= (c.1191C>T) pathogenic?

FREM2 p.Pro397= (c.1191C>T) is classified Conflicting classifications of pathogenicity in FREM2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0241%, nfe); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Pro397= (c.1191C>T)?

FREM2 p.Pro397= (c.1191C>T) is associated with Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Pro397= (c.1191C>T) in the general population?

FREM2 p.Pro397= (c.1191C>T) is ultra-rare (popmax 0.0241%, nfe) (gnomAD).

FREM2 p.Pro397=

c.1191C>T · rs199831729 · VCV311944

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0241%, nfe)

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 -3.7	GERP -5.4
Overall
CADD	0.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0241% European (non-Finnish) · 284/1,179,930 alleles

Filtering AF 0.0217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.019% 307/1,613,946 alleles · ultra-rare exomes 276/1,461,686 · genomes 31/152,260 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0241%	4,155
Middle Eastern	0.0165%	6,060
Admixed American	0.015%	6,668
Remaining individualsnot grpmax-eligible	0.0144%	6,944
African / African-American	0.00533%	18,759

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.Pro397=
Coding: c.1191C>T
MANE Select: NM_207361
dbSNP: rs199831729
Type: single nucleotide variant
Location: chr13:38688535 (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

Similar variants

FREM2 p.Pro397Ala 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-pro397 (accessed [today's date]).

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