Is IMPDH2 p.Ser159Phe (c.476C>T) pathogenic?

IMPDH2 p.Ser159Phe (c.476C>T) is classified Uncertain significance in IMPDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-18). AlphaMissense: likely pathogenic (0.9924); Very rare (popmax 0.00133%, afr).

How common is IMPDH2 p.Ser159Phe (c.476C>T) in the general population?

IMPDH2 p.Ser159Phe (c.476C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about IMPDH2 p.Ser159Phe (c.476C>T)?

AlphaMissense predicts likely pathogenic (score 0.9924) — an in-silico prediction, not a clinical call.

IMPDH2 p.Ser159Phe

c.476C>T · VCV3369709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9924 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9924	likely pathogenic
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -14.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/74,932 alleles

Overall 6.2e-05% 1/1,614,076 alleles · very rare exomes 0/1,461,884 · genomes 1/152,192 · joint denominator

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.Ser159Phe
Coding: c.476C>T
MANE Select: NM_000884
Type: single nucleotide variant
Location: chr3:49027765 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07 · 25 PDB
Residue 159: the cbs 1 domain

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-ser159phe (accessed [today's date]).

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