Is GREM1 p.Pro35= (c.105G>T) pathogenic?

GREM1 p.Pro35= (c.105G>T) is classified Likely benign in GREM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-04). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with GREM1 p.Pro35= (c.105G>T)?

GREM1 p.Pro35= (c.105G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is GREM1 p.Pro35= (c.105G>T) in the general population?

GREM1 p.Pro35= (c.105G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

GREM1 p.Pro35=

c.105G>T · rs746525315 · VCV1697741

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary neoplastic syndrome

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 -5.9	GERP -3.7
Overall
CADD	0.593	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,966 alleles

Overall 6.2e-05% 1/1,613,644 alleles · very rare exomes 0/1,461,592 · genomes 1/152,052 · 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: GREM1
Protein: p.Pro35=
Coding: c.105G>T
MANE Select: NM_013372
dbSNP: rs746525315
Type: single nucleotide variant
Location: chr15:32730795 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI 0.23 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 2 PDB
Residue 35: the 'disordered' region

Full GREM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GREM1 p.Pro35Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
GREM1 p.Pro35Gln Uncertain significance ★ ⚠ same residue
GREM1 p.Pro35Leu Uncertain significance ★ ⚠ same residue
GREM1 p.Pro35Ser Uncertain significance ★ ⚠ same residue
GREM1 p.Arg64Trp Uncertain significance ★★ ⚠ same condition
GREM1 p.Ile103Val Uncertain significance ★★ ⚠ same condition
GREM1 p.Lys26Arg Uncertain significance ★★ ⚠ same condition
GREM1 p.Ser49Trp 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/grem1-p-pro35 (accessed [today's date]).

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