Is AIP p.Val49Met (c.145G>A) pathogenic?

AIP p.Val49Met (c.145G>A) is classified Conflicting classifications of pathogenicity in AIP (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1406); Rare (popmax 0.256%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with AIP p.Val49Met (c.145G>A)?

AIP p.Val49Met (c.145G>A) is associated with hereditary neoplastic syndrome, growth hormone secreting pituitary adenoma 1 (ClinVar).

How common is AIP p.Val49Met (c.145G>A) in the general population?

AIP p.Val49Met (c.145G>A) is rare (popmax 0.256%, eas) (gnomAD).

What do computational predictors say about AIP p.Val49Met (c.145G>A)?

AlphaMissense predicts likely benign (score 0.1406) — an in-silico prediction, not a clinical call.

AIP p.Val49Met

c.145G>A · rs1063385 · VCV41164

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1406 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.256%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1406	likely benign
REVEL	0.708	pathogenic-leaning
SaProt	LLR -9.44	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.6, phastCons 1
Overall
CADD	23.0	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 0.256% East Asian · 115/44,888 alleles

Filtering AF 0.218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.204%

Overall 0.0147% 237/1,613,944 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.256%	390
Ashkenazi Jewishnot grpmax-eligible	0.196%	510
Admixed American	0.0717%	1,396
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.00133%	74,934
European (non-Finnish)	0.000847%	118,005

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.Val49Met
Coding: c.145G>A
MANE Select: NM_003977
dbSNP: rs1063385
Type: single nucleotide variant
Location: chr11:67487051 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 91.09 · 5 PDB
Residue 49: the ppiase fkbp-type domain; a β-strand; a UniProt-annotated variant site (in pita1; uncertain significance)

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

Similar variants

AIP p.Val49Leu Uncertain significance ★★ ⚠ same residue
AIP p.Val49= Likely benign 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
AIP p.Gln126Ter Pathogenic ★★ same condition
AIP p.Gln14Ter 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-val49met (accessed [today's date]).

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