Is AIP p.His135Arg (c.404A>G) pathogenic?

AIP p.His135Arg (c.404A>G) is classified Uncertain significance in AIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-18). AlphaMissense: ambiguous (0.3424); Very rare (popmax 0.00333%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with AIP p.His135Arg (c.404A>G)?

AIP p.His135Arg (c.404A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is AIP p.His135Arg (c.404A>G) in the general population?

AIP p.His135Arg (c.404A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about AIP p.His135Arg (c.404A>G)?

AlphaMissense predicts ambiguous (score 0.3424) — an in-silico prediction, not a clinical call.

AIP p.His135Arg

c.404A>G · rs769856618 · VCV1016223

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3424 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3424	ambiguous
REVEL	0.66	pathogenic-leaning
SaProt	LLR -12.94	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2, phastCons 1
Overall
CADD	22.2	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 0.00333% Admixed American · 2/60,032 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000205% 3/1,460,590 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,016
European (non-Finnish)	8.47e-05%	1,179,944

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.His135Arg
Coding: c.404A>G
MANE Select: NM_017900 · reported on NM_003977
dbSNP: rs769856618
Type: single nucleotide variant
Location: chr11:67489391 (GRCh38)
Structure: AlphaFold pLDDT 70.14 · 81 PDB
Residue 135: an α-helix

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.His135Tyr Conflicting classifications of pathogenicity ★ ⚠ 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
AIP p.Gln217Ter 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-his135arg (accessed [today's date]).

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