Is FREM2 p.Asp750= (c.2250C>T) pathogenic?

FREM2 p.Asp750= (c.2250C>T) is classified Benign in FREM2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 18.5%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Asp750= (c.2250C>T)?

FREM2 p.Asp750= (c.2250C>T) is associated with Fraser syndrome 2, Fraser syndrome 1 (ClinVar).

FREM2 p.Asp750=

Q: How common is FREM2 p.Asp750= (c.2250C>T) in the general population?

FREM2 p.Asp750= (c.2250C>T) is common (popmax 18.5%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2250C>T · rs41292755 · VCV193537

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 18.5%, sas) — too common for a highly-penetrant pathogenic allele

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 -1.4	GERP -5.2
Overall
CADD	5.428	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18.5% South Asian · 16,816/90,884 alleles

Filtering AF 18.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.2%

Overall 10.7% 172,318/1,612,632 alleles · common exomes 159,806/1,460,498 · genomes 12,512/152,134 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	18.5%	5
East Asian	12.7%	8
European (non-Finnish)	10.8%	9
Admixed American	10.4%	10
Remaining individualsnot grpmax-eligible	10.4%	10
Finnishnot grpmax-eligible	9.25%	11
Amishnot grpmax-eligible	8.55%	12
Middle Eastern	8.36%	12
Ashkenazi Jewishnot grpmax-eligible	7.74%	13
African / African-American	1.83%	55

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.Asp750=
Coding: c.2250C>T
MANE Select: NM_207361
dbSNP: rs41292755
Type: single nucleotide variant
Location: chr13:38689594 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 750: 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: Fraser syndrome 1

Similar variants

FREM2 p.Asp750Glu Uncertain significance ★★ same residue
FREM2 p.Asp750Phe Uncertain significance ★ same residue
FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Arg2243Ter 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

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-asp750 (accessed [today's date]).

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