Is GEN1 p.Pro481Ser (c.1441C>T) pathogenic?

GEN1 p.Pro481Ser (c.1441C>T) is classified Conflicting classifications of pathogenicity in GEN1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.0654); Ultra-rare (popmax 0.036%, nfe).

How common is GEN1 p.Pro481Ser (c.1441C>T) in the general population?

GEN1 p.Pro481Ser (c.1441C>T) is ultra-rare (popmax 0.036%, nfe) (gnomAD).

What do computational predictors say about GEN1 p.Pro481Ser (c.1441C>T)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

GEN1 p.Pro481Ser

c.1441C>T · rs374176559 · VCV1021651

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -4.2, phastCons 0.002
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.76 · regional, not allelic
Overall
CADD	1.18	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.036% European (non-Finnish) · 422/1,171,984 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.032%

Overall 0.0272% 434/1,597,830 alleles · ultra-rare exomes 413/1,445,746 · genomes 21/152,084 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.036%	2,777
Remaining individualsnot grpmax-eligible	0.0081%	12,352
African / African-American	0.00675%	14,824
Admixed American	0.00174%	57,564
Finnishnot grpmax-eligible	0.00157%	63,746

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.Pro481Ser
Coding: c.1441C>T
MANE Select: NM_001130009
dbSNP: rs374176559
Type: single nucleotide variant
Location: chr2:17780653 (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

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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
GEN1 p.Ala448Thr Uncertain significance ★★ ⚠ same type
GEN1 p.Ala454Thr 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-pro481ser (accessed [today's date]).

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