Is IAPP p.Arg33Gln (c.98G>A) pathogenic?

IAPP p.Arg33Gln (c.98G>A) is classified Uncertain significance in IAPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: likely benign (0.1304); Very rare (popmax 0.0022%, sas).

How common is IAPP p.Arg33Gln (c.98G>A) in the general population?

IAPP p.Arg33Gln (c.98G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about IAPP p.Arg33Gln (c.98G>A)?

AlphaMissense predicts likely benign (score 0.1304) — an in-silico prediction, not a clinical call.

IAPP p.Arg33Gln

c.98G>A · VCV4037000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1304 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1304	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor loss, 17 bp away · masked 0 · deltas
Pangolin	Δ0.22	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.42	GERP -0.45, phastCons 0.027
Regional constraint	o/e 1.08	unconstrained · MANE · 5,071 bp · p 0.4 · regional, not allelic
Overall
CADD	23.1	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 0.0022% South Asian · 2/91,076 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00161% 26/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,538
European (non-Finnish)	0.00186%	53,637
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00134%	74,894

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: IAPP
Protein: p.Arg33Gln
Coding: c.98G>A
MANE Select: NM_000415
Type: single nucleotide variant
Location: chr12:21378254 (GRCh38)
Gene constraint: LOEUF 1.499 · pLI 0.35 (gnomAD)
Structure: AlphaFold pLDDT 78.59 · 80 PDB

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

Similar variants

IAPP p.Arg73Lys Uncertain significance ★ same type
IAPP p.Asn47Ser Uncertain significance ★ ⚠ same type
IAPP p.Leu13Phe Uncertain significance ★ ⚠ same type
IAPP p.Thr23Ile 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/iapp-p-arg33gln (accessed [today's date]).

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