Is FREM2 p.Pro1656= (c.4968C>T) pathogenic?

FREM2 p.Pro1656= (c.4968C>T) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Absent from gnomAD v4.1; Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Pro1656= (c.4968C>T)?

FREM2 p.Pro1656= (c.4968C>T) is associated with Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Pro1656= (c.4968C>T) in the general population?

FREM2 p.Pro1656= (c.4968C>T) is absent from gnomAD v4.1 (gnomAD).

FREM2 p.Pro1656=

c.4968C>T · rs886050190 · VCV311985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 0.085	GERP -0.55, phastCons 0.92
Overall
CADD	9.677	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FREM2
Protein: p.Pro1656=
Coding: c.4968C>T
MANE Select: NM_207361
dbSNP: rs886050190
Type: single nucleotide variant
Location: chr13:38692312 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 1656: 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.Pro1656Ser 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-pro1656 (accessed [today's date]).

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