Is IMP4 p.Pro158Leu (c.473C>T) pathogenic?

IMP4 p.Pro158Leu (c.473C>T) is classified Uncertain significance in IMP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). AlphaMissense: likely pathogenic (0.9635); Ultra-rare (popmax 0.0253%, sas).

How common is IMP4 p.Pro158Leu (c.473C>T) in the general population?

IMP4 p.Pro158Leu (c.473C>T) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about IMP4 p.Pro158Leu (c.473C>T)?

AlphaMissense predicts likely pathogenic (score 0.9635) — an in-silico prediction, not a clinical call.

IMP4 p.Pro158Leu

c.473C>T · rs752098379 · VCV3109550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9635 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9635	likely pathogenic
REVEL	0.636	indeterminate
SaProt	LLR -14.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,532 bp · p 0.15 · regional, not allelic
Overall
CADD	29.1	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 0.0253% South Asian · 23/91,084 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00149% 24/1,613,892 alleles · ultra-rare exomes 22/1,461,724 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,960
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: IMP4
Protein: p.Pro158Leu
Coding: c.473C>T
MANE Select: NM_033416
dbSNP: rs752098379
Type: single nucleotide variant
Location: chr2:130345812 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.47 · 3 PDB
Residue 158: the brix domain

Full IMP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IMP4 p.Ala21Val Uncertain significance ★ ⚠ same type
IMP4 p.Ala282Thr Uncertain significance ★ ⚠ same type
IMP4 p.Arg126Gln Uncertain significance ★ ⚠ same type
IMP4 p.Arg170Trp Uncertain significance ★ ⚠ same type
IMP4 p.Arg194Cys Uncertain significance ★ ⚠ same type
IMP4 p.Arg198Gln Uncertain significance ★ ⚠ same type
IMP4 p.Arg204Gln Uncertain significance ★ ⚠ same type
IMP4 p.Arg216Gln 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/imp4-p-pro158leu (accessed [today's date]).

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