Is IMP4 p.Arg28Ser (c.84G>C) pathogenic?

IMP4 p.Arg28Ser (c.84G>C) is classified Uncertain significance in IMP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: ambiguous (0.4831); Very rare (popmax 0.00803%, nfe).

How common is IMP4 p.Arg28Ser (c.84G>C) in the general population?

IMP4 p.Arg28Ser (c.84G>C) is very rare (popmax 0.00803%, nfe) (gnomAD).

What do computational predictors say about IMP4 p.Arg28Ser (c.84G>C)?

AlphaMissense predicts ambiguous (score 0.4831) — an in-silico prediction, not a clinical call.

IMP4 p.Arg28Ser

c.84G>C · VCV3285959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00803%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4831	ambiguous
REVEL	0.14	moderately benign-leaning
SaProt	LLR -12.29	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,532 bp · p 0.15 · regional, not allelic
Overall
CADD	21.6	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 0.00803% European (non-Finnish) · 92/1,146,002 alleles

Filtering AF 0.00667% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00618%

Overall 0.00639% 99/1,549,914 alleles · very rare exomes 95/1,397,686 · genomes 4/152,228 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00803%	12,457
Remaining individualsnot grpmax-eligible	0.00667%	15,002
African / African-American	0.00411%	24,341

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.Arg28Ser
Coding: c.84G>C
MANE Select: NM_033416
Type: single nucleotide variant
Location: chr2:130343166 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.47 · 3 PDB
Residue 28: an α-helix

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-arg28ser (accessed [today's date]).

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