Is FREM2 p.Ala63fs (c.187del) pathogenic?

FREM2 p.Ala63fs (c.187del) is classified Pathogenic in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). Very rare (popmax 6.25e-05%).

How common is FREM2 p.Ala63fs (c.187del) in the general population?

FREM2 p.Ala63fs (c.187del) is very rare (popmax 6.25e-05%) (gnomAD).

FREM2 p.Ala63fs

c.187del · rs2541347720 · VCV2803781

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.25e-05%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.59	GERP -2.7

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.25e-05%

Overall 6.25e-05% 1/1,598,814 alleles · very rare exomes 1/1,446,474 · genomes 0/152,340 · joint denominator

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.Ala63fs
Coding: c.187del
MANE Select: NM_207361
dbSNP: rs2541347720
Type: Deletion
Location: chr13:38687527 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)

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

Similar variants

FREM2 p.Ala1996fs Pathogenic/Likely pathogenic ★★ same type
FREM2 p.Gln1190fs Pathogenic/Likely pathogenic ★★ same type
FREM2 p.His945fs Pathogenic/Likely pathogenic ★★ same type
FREM2 p.Leu2493fs Pathogenic/Likely pathogenic ★★ same type
FREM2 c.6379+19del Benign/Likely benign ★★ same type
FREM2 c.7520-5del Benign/Likely benign ★★ same type
FREM2 c.7520-6_7520-2del Likely pathogenic ★ same type
FREM2 p.Ala2962fs 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-ala63fs (accessed [today's date]).

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