Is AIP p.Arg325Trp (c.973C>T) pathogenic?

AIP p.Arg325Trp (c.973C>T) is classified Uncertain significance in AIP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.2205); Ultra-rare (popmax 0.012%, afr); Associated with growth hormone secreting pituitary adenoma 1.

What condition is associated with AIP p.Arg325Trp (c.973C>T)?

AIP p.Arg325Trp (c.973C>T) is associated with growth hormone secreting pituitary adenoma 1, hereditary neoplastic syndrome (ClinVar).

How common is AIP p.Arg325Trp (c.973C>T) in the general population?

AIP p.Arg325Trp (c.973C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is Familial isolated pituitary adenoma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AIP p.Arg325Trp (c.973C>T)?

AlphaMissense predicts likely benign (score 0.2205) — an in-silico prediction, not a clinical call.

AIP p.Arg325Trp

c.973C>T · rs765927395 · VCV823446

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2205 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

growth hormone secreting pituitary adenoma 1

Computational evidence

Protein change
AlphaMissense	0.2205	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -11.80	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.74, phastCons 1
Overall
CADD	24.3	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 0.012% African / African-American · 9/74,846 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.0023% 37/1,606,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,316
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,482
South Asian	0.00332%	30,088
East Asian	0.00224%	44,610
European (non-Finnish)	0.00178%	56,061
Admixed American	0.00169%	59,110
Remaining individualsnot grpmax-eligible	0.00161%	62,196

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.Arg325Trp
Coding: c.973C>T
MANE Select: NM_017900 · reported on NM_003977
dbSNP: rs765927395
Type: single nucleotide variant
Location: chr11:67490973 (GRCh38)
Structure: AlphaFold pLDDT 70.14 · 81 PDB

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

Disease context

growth hormone secreting pituitary adenoma 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Familial isolated pituitary adenoma (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Elderly, Infancy

Similar variants

AIP p.Arg325Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
AIP p.Arg325= Likely benign ★ same residue
AIP p.Arg325fs Uncertain significance ★★ same residue
AIP p.Arg325Pro Uncertain significance ★ ⚠ same residue
AIP p.Arg271Trp Pathogenic/Likely pathogenic ★★ same condition
AIP p.Arg304Ter Pathogenic ★★ same condition
AIP p.Arg81Ter Pathogenic ★★ same condition
AIP p.Cys238Tyr Likely 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-arg325trp (accessed [today's date]).

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