Is GEN1 p.Ala558= (c.1674T>A) pathogenic?

GEN1 p.Ala558= (c.1674T>A) is classified Likely benign in GEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-21). Ultra-rare (popmax 0.056%, afr).

How common is GEN1 p.Ala558= (c.1674T>A) in the general population?

GEN1 p.Ala558= (c.1674T>A) is ultra-rare (popmax 0.056%, afr) (gnomAD).

GEN1 p.Ala558=

c.1674T>A · rs138268141 · VCV1149112

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.056%, afr)

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 1.4	GERP -0.37, phastCons 0.005
Overall
CADD	6.545	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.056% African / African-American · 42/75,060 alleles

Filtering AF 0.0425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00266% 43/1,613,904 alleles · ultra-rare exomes 15/1,461,562 · genomes 28/152,342 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.056%	1,787
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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.Ala558=
Coding: c.1674T>A
MANE Select: NM_001130009
dbSNP: rs138268141
Type: single nucleotide variant
Location: chr2:17780886 (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.Ala558Pro Uncertain significance ★ ⚠ same residue
GEN1 p.Ala558Val 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-ala558 (accessed [today's date]).

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