Is GEN1 p.Ile400Val (c.1198A>G) pathogenic?

GEN1 p.Ile400Val (c.1198A>G) is classified Uncertain significance in GEN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-24). AlphaMissense: likely benign (0.0622); Ultra-rare (popmax 0.0157%, eas).

How common is GEN1 p.Ile400Val (c.1198A>G) in the general population?

GEN1 p.Ile400Val (c.1198A>G) is ultra-rare (popmax 0.0157%, eas) (gnomAD).

What do computational predictors say about GEN1 p.Ile400Val (c.1198A>G)?

AlphaMissense predicts likely benign (score 0.0622) — an in-silico prediction, not a clinical call.

GEN1 p.Ile400Val

c.1198A>G · rs780793654 · VCV1430873

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0622 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0622	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -5.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.33	donor loss · deltas
Pangolin	Δ0.31	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.1	GERP -0.25
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.76 · regional, not allelic
Overall
CADD	13.01	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0157% East Asian · 7/44,460 alleles

Filtering AF 0.00732% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00519%

Overall 0.000563% 9/1,599,318 alleles · ultra-rare exomes 7/1,447,146 · genomes 2/152,172 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0157%	6,351
Remaining individualsnot grpmax-eligible	0.00162%	61,772
European (non-Finnish)	8.53e-05%	1,172,992

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.Ile400Val
Coding: c.1198A>G
MANE Select: NM_001130009
dbSNP: rs780793654
Type: single nucleotide variant
Location: chr2:17774397 (GRCh38)
Gene constraint: LOEUF 1.422 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 1 PDB
Residue 400: the 'chromodomain' region; a β-strand

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

Similar variants

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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-ile400val (accessed [today's date]).

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