Is FREM2 p.Pro2685= (c.8055C>T) pathogenic?

FREM2 p.Pro2685= (c.8055C>T) is classified Likely benign in FREM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-18). Ultra-rare (popmax 0.0134%, eas).

How common is FREM2 p.Pro2685= (c.8055C>T) in the general population?

FREM2 p.Pro2685= (c.8055C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

FREM2 p.Pro2685=

c.8055C>T · rs148758281 · VCV2071840

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

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 -20	GERP -5
Overall
CADD	0.005	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,886 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00198% 32/1,613,874 alleles · ultra-rare exomes 25/1,461,734 · genomes 7/152,140 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.024%	4,165
East Asiangrpmax	0.0134%	7,481
African / African-American	0.00801%	12,485
Admixed American	0.00333%	30,000
South Asian	0.0011%	91,088
European (non-Finnish)	0.00017%	589,960

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2685=
Coding: c.8055C>T
MANE Select: NM_207361
dbSNP: rs148758281
Type: single nucleotide variant
Location: chr13:38872813 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2685: a UniProt-annotated variant site (in cryptop)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FREM2 c.5263+1G>A Likely pathogenic ★★ same type
FREM2 c.6925+1G>T Likely pathogenic ★★ same type
FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same type
FREM2 p.Arg2243Ter Pathogenic/Likely pathogenic ★★ same type
FREM2 p.Arg638Ter Likely pathogenic ★★ same type
FREM2 p.Arg736Ter Pathogenic ★★ same type
FREM2 p.Arg809Ter Pathogenic ★★ same type
FREM2 p.Gln1051Ter Pathogenic/Likely pathogenic ★★ same type

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-pro2685 (accessed [today's date]).

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