Is GEN1 p.Pro868= (c.2604A>G) pathogenic?

GEN1 p.Pro868= (c.2604A>G) is classified Likely benign in GEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-02). Very rare (popmax 0.00669%, eas).

How common is GEN1 p.Pro868= (c.2604A>G) in the general population?

GEN1 p.Pro868= (c.2604A>G) is very rare (popmax 0.00669%, eas) (gnomAD).

GEN1 p.Pro868=

c.2604A>G · rs776410983 · VCV1142768

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP -1.6
Overall
CADD	1.481	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,844 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000248% 4/1,612,434 alleles · very rare exomes 3/1,460,218 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,948
Remaining individualsnot grpmax-eligible	0.0016%	62,406

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: GEN1
Protein: p.Pro868=
Coding: c.2604A>G
MANE Select: NM_001130009
dbSNP: rs776410983
Type: single nucleotide variant
Location: chr2:17781816 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 1 PDB

Full GEN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GEN1 p.Pro868Ala Uncertain significance ★ ⚠ same residue
GEN1 p.Pro868fs Uncertain significance ★ same residue
GEN1 c.1264+1G>T Uncertain significance ★★ same type
GEN1 c.953+4A>G Uncertain significance ★★ same type
GEN1 p.Ala135Ser Uncertain significance ★★ ⚠ same type
GEN1 p.Ala197Thr Uncertain significance ★★ ⚠ same type
GEN1 p.Ala320Pro Uncertain significance ★★ ⚠ same type
GEN1 p.Ala447Val Uncertain significance ★★ ⚠ 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/gen1-p-pro868 (accessed [today's date]).

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