Is IMPDH2 p.Ile453Val (c.1357A>G) pathogenic?

IMPDH2 p.Ile453Val (c.1357A>G) is classified Uncertain significance in IMPDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-14). AlphaMissense: likely benign (0.0795); Very rare (popmax 0.00267%, afr).

How common is IMPDH2 p.Ile453Val (c.1357A>G) in the general population?

IMPDH2 p.Ile453Val (c.1357A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about IMPDH2 p.Ile453Val (c.1357A>G)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

IMPDH2 p.Ile453Val

c.1357A>G · rs1177890498 · VCV2311691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.41	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 4,964 bp · p 1e-16 · regional, not allelic
Overall
CADD	24.6	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 0.00267% African / African-American · 2/75,034 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,176 alleles · very rare exomes 4/1,461,892 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,517
European (non-Finnish)	0.000169%	590,012

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: IMPDH2
Protein: p.Ile453Val
Coding: c.1357A>G
MANE Select: NM_000884
dbSNP: rs1177890498
Type: single nucleotide variant
Location: chr3:49024741 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07 · 25 PDB
Residue 453: an α-helix

Full IMPDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

QRICH1 p.Arg652Ter Pathogenic ★★ same type
IMPDH2 p.Ile88Thr Uncertain significance ★★ ⚠ same type
IMPDH2 c.819+10T>C Benign ★★ same type
IMPDH2 c.99-4G>A Benign/Likely benign ★★ same type
IMPDH2 p.Asp239Val Likely pathogenic ★ same type
IMPDH2 p.Gly113Glu Likely pathogenic ★ same type
IMPDH2 p.Lys238Arg Likely pathogenic ★ ⚠ same type
IMPDH2 c.147+5G>A 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/impdh2-p-ile453val (accessed [today's date]).

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