Is IMPDH2 p.Pro123Arg (c.368C>G) pathogenic?

IMPDH2 p.Pro123Arg (c.368C>G) is classified Uncertain significance in IMPDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: ambiguous (0.4452); Very rare (popmax 0.00339%, nfe).

How common is IMPDH2 p.Pro123Arg (c.368C>G) in the general population?

IMPDH2 p.Pro123Arg (c.368C>G) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about IMPDH2 p.Pro123Arg (c.368C>G)?

AlphaMissense predicts ambiguous (score 0.4452) — an in-silico prediction, not a clinical call.

IMPDH2 p.Pro123Arg

c.368C>G · rs142797363 · VCV2359650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4452 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4452	ambiguous
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -13.51	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 4,964 bp · p 1e-16 · regional, not allelic
Overall
CADD	31.0	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 0.00339% European (non-Finnish) · 40/1,180,018 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00266% 43/1,614,070 alleles · very rare exomes 40/1,461,848 · genomes 3/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,500
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,930

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.Pro123Arg
Coding: c.368C>G
MANE Select: NM_000884
dbSNP: rs142797363
Type: single nucleotide variant
Location: chr3:49027873 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07 · 25 PDB
Residue 123: the cbs 1 domain; a β-strand

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-pro123arg (accessed [today's date]).

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