Is FREM2 p.Arg809Ter (c.2425C>T) pathogenic?

FREM2 p.Arg809Ter (c.2425C>T) is classified Pathogenic in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-09). Very rare (popmax 0.0011%, sas); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Arg809Ter (c.2425C>T)?

FREM2 p.Arg809Ter (c.2425C>T) is associated with Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Arg809Ter (c.2425C>T) in the general population?

FREM2 p.Arg809Ter (c.2425C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

FREM2 p.Arg809Ter

c.2425C>T · rs761047751 · VCV2799204

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Fraser syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 24
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.4	GERP -0.45, phastCons 0.004
Overall
CADD	35.0	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 0.0011% South Asian · 1/90,904 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,166 alleles · very rare exomes 5/1,460,964 · genomes 0/152,202 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,904
European (non-Finnish)	0.000339%	294,894

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.Arg809Ter
Coding: c.2425C>T
MANE Select: NM_207361
dbSNP: rs761047751
Type: single nucleotide variant
Location: chr13:38689769 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 809: 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.Arg809Gln Likely benign 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.Gln1051Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Gln717Ter Likely pathogenic ★★ same condition
FREM2 p.Ala1659Thr Uncertain significance ★★ ⚠ same condition
FREM2 p.Ala1664Val 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-arg809ter (accessed [today's date]).

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