Is GEN1 p.Ala447= (c.1341A>G) pathogenic?

GEN1 p.Ala447= (c.1341A>G) is classified Benign in GEN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 11.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with GEN1 p.Ala447= (c.1341A>G)?

GEN1 p.Ala447= (c.1341A>G) is associated with hereditary neoplastic syndrome (ClinVar).

GEN1 p.Ala447=

Q: How common is GEN1 p.Ala447= (c.1341A>G) in the general population?

GEN1 p.Ala447= (c.1341A>G) is common (popmax 11.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1341A>G · rs16983864 · VCV1169751

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 11.4%, afr) — too common for a highly-penetrant pathogenic allele

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 1.6	GERP -1.5, phastCons 1
Overall
CADD	8.713	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.4% African / African-American · 8,562/74,890 alleles

Filtering AF 11.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.1%

Overall 1.12% 18,072/1,609,716 alleles · common exomes 12,473/1,457,356 · genomes 5,599/152,360 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.4%	9
East Asian	3.93%	25
South Asian	1.41%	71
Remaining individualsnot grpmax-eligible	1.26%	79
Middle Eastern	0.826%	121
Admixed American	0.792%	126
Ashkenazi Jewishnot grpmax-eligible	0.724%	138
European (non-Finnish)	0.411%	243
Finnishnot grpmax-eligible	0.164%	609

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.Ala447=
Coding: c.1341A>G
MANE Select: NM_001130009
dbSNP: rs16983864
Type: single nucleotide variant
Location: chr2:17780054 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 1 PDB
Residue 447: the 'chromodomain' region; an α-helix

Full GEN1 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

GEN1 p.Ala447Val Uncertain significance ★★ ⚠ same residue
GEN1 c.953+4A>G Uncertain significance ★★ same condition
GEN1 c.162-24G>A Benign ★★ same condition
GEN1 c.162-36T>A Benign ★★ same condition
GEN1 c.348+7A>G Benign ★★ same condition
GEN1 c.990+22C>G Benign ★★ same condition
GEN1 p.Asn143Ser Benign ★★ ⚠ same condition
GEN1 p.Glu657= Benign ★★ 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/gen1-p-ala447 (accessed [today's date]).

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