Is AIP p.Glu246Lys (c.736G>A) pathogenic?

AIP p.Glu246Lys (c.736G>A) is classified Uncertain significance in AIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.6524); Very rare (popmax 0.00144%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with AIP p.Glu246Lys (c.736G>A)?

AIP p.Glu246Lys (c.736G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is AIP p.Glu246Lys (c.736G>A) in the general population?

AIP p.Glu246Lys (c.736G>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about AIP p.Glu246Lys (c.736G>A)?

AlphaMissense predicts likely pathogenic (score 0.6524) — an in-silico prediction, not a clinical call.

AIP p.Glu246Lys

c.736G>A · rs775566997 · VCV1023109

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6524 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6524	likely pathogenic
REVEL	0.354	indeterminate
SaProt	LLR -12.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00144% European (non-Finnish) · 17/1,180,024 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00105% 17/1,612,348 alleles · very rare

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.Glu246Lys
Coding: c.736G>A
MANE Select: NM_017900 · reported on NM_003977
dbSNP: rs775566997
Type: single nucleotide variant
Location: chr11:67490406 (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

Similar variants

AIP p.Glu246Asp Uncertain significance ★★ ⚠ same residue
AIP p.Glu246= Likely benign ★★ same residue
AIP p.Glu246Ter Pathogenic ★ 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

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-glu246lys (accessed [today's date]).

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