Is GREM1 p.Pro69= (c.207C>T) pathogenic?

GREM1 p.Pro69= (c.207C>T) is classified Likely benign in GREM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-12). Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with GREM1 p.Pro69= (c.207C>T)?

GREM1 p.Pro69= (c.207C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is GREM1 p.Pro69= (c.207C>T) in the general population?

GREM1 p.Pro69= (c.207C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

GREM1 p.Pro69=

c.207C>T · VCV3282660

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-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 -20	GERP -3.1
Overall
CADD	0.008	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,832 alleles

Overall 0.000124% 2/1,613,550 alleles · very rare exomes 2/1,461,356 · genomes 0/152,194 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)grpmax	8.48e-05%	1,179,832

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: GREM1
Protein: p.Pro69=
Coding: c.207C>T
MANE Select: NM_013372
Type: single nucleotide variant
Location: chr15:32730897 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI 0.23 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 2 PDB
Residue 69: 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.Pro69Ala Uncertain significance ★ ⚠ same residue
GREM1 p.Pro69His Uncertain significance ★ ⚠ same residue
GREM1 p.Pro69Ser 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
GREM1 p.Thr155Ala 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-pro69 (accessed [today's date]).

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