Is AIP p.Arg304Gln (c.911G>A) pathogenic?

AIP p.Arg304Gln (c.911G>A) is classified Conflicting classifications of pathogenicity in AIP (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.112); Ultra-rare (popmax 0.0953%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with AIP p.Arg304Gln (c.911G>A)?

AIP p.Arg304Gln (c.911G>A) is associated with hereditary neoplastic syndrome, growth hormone secreting pituitary adenoma 1, Cushing disease due to pituitary adenoma (ClinVar).

How common is AIP p.Arg304Gln (c.911G>A) in the general population?

AIP p.Arg304Gln (c.911G>A) is ultra-rare (popmax 0.0953%, nfe) (gnomAD).

What do computational predictors say about AIP p.Arg304Gln (c.911G>A)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

AIP p.Arg304Gln

c.911G>A · rs104894190 · VCV4893

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0953%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP -0.42, phastCons 1
Overall
CADD	23.5	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 0.0953% European (non-Finnish) · 1,125/1,179,906 alleles

Filtering AF 0.0907% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0889%

Overall 0.115% 1,852/1,612,586 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.87%	54
Remaining individualsnot grpmax-eligible	0.19%	525
European (non-Finnish)grpmax	0.0953%	1,049
Admixed American	0.0633%	1,579
Middle Eastern	0.0495%	2,020
African / African-American	0.00933%	10,723
East Asian	0.00669%	14,959
Finnishnot grpmax-eligible	0.00479%	20,895
South Asian	0.0011%	91,046

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AIP
Protein: p.Arg304Gln
Coding: c.911G>A
MANE Select: NM_017900 · reported on NM_003977
dbSNP: rs104894190
Type: single nucleotide variant
Location: chr11:67490911 (GRCh38)
Structure: AlphaFold pLDDT 70.14 · 81 PDB

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: growth hormone secreting pituitary adenoma 1 Cushing disease due to pituitary adenoma

Similar variants

AIP p.Arg304Ter Pathogenic ★★ same residue
AIP p.Arg271Trp Pathogenic/Likely pathogenic ★★ same condition
AIP p.Arg81Ter Pathogenic ★★ same condition
AIP p.Cys238Tyr Likely pathogenic ★★ same condition
AIP p.Gln126Ter Pathogenic ★★ same condition
AIP p.Gln14Ter Pathogenic ★★ same condition
AIP p.Gln217Ter Pathogenic ★★ same condition
AIP p.Trp168Ter Pathogenic ★★ same condition

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/aip-p-arg304gln (accessed [today's date]).

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